Compounds and methods for preventing or treating sensory hair cell death

ABSTRACT

Disclosed herein are compounds, and pharmaceutical compositions that include such compounds, for preventing or treating hearing loss. The compounds and pharmaceutical compositions described herein prevent or treat hair cell death. In addition, the compounds and pharmaceutical compositions described herein protect against kidney damage in an individual receiving an aminoglycoside antibiotic. Methods of using the compounds, alone or in combination with other therapeutic agents, are also disclosed.

CROSS-REFERENCE

This application claims the benefit of U.S. provisional application Ser.No. 62/113,245, filed Feb. 6, 2015, which is incorporated by referencein its entirety.

STATEMENT AS TO FEDERALLY SPONSORED RESEARCH

This invention was made with government support under Grants 5U01NS074506, 1R01 DC009807, and 1R43 DC013930-01 awarded by the NationalInstitutes of Health. The government has certain rights in theinvention.

BACKGROUND

Aminoglycosides are clinically used drugs that cause dose-dependentsensorineural hearing loss (Smith et al., New Engl J Med, (1977)296:349-53) and are known to kill hair cells in the mammalian inner ear(Theopold, Acta Otolaryngol (1977) 84:57-64). In the U.S. over 2,000,000people receive treatment with aminoglycosides per year. The clinicalefficacy of these antibiotics in treating drug-resistant bacterialinfections and their low cost account for their continued worldwide usedespite their known ototoxicity liability. The incidence ofvestibulotoxic effects of such drugs on patient populations has beenless well studied. Estimates range between 3% and 6% with continuedreports in the literature of patients with aminoglycoside inducedvestibulotoxicity (Dhanireddy et al., Arch Otolarngol Head Neck Surg(2005) 131:46-48). Other clinically important and commonly used drugsalso have documented ototoxic effects, including cisplatin (Allen, etal, Otolaryngol Head Neck Surg (1998) 118:584-588), loop diuretics(Greenberg, Am J Med Sci, (2000) 319:10-24), antimalarial sesquiterpenelactone endoperoxides (i.e., artemesinins) (Toovey and Jamieson, Trans RSoc Trop Med Hyg (2004) 98:261-7), antimalarial quinines (Claessen, etal., Trop Med Int Health, (1998) 3:482-9), salicylates (Matz, Ann OtolRhinol Laryngol Suppl (1990) 148:39-41), and interferon polypeptides(Formann, et al., Am J Gastroenterol (2004) 99:873-77).

BRIEF SUMMARY OF THE INVENTION

Described herein are compounds of Formula (I), Formula (Ia), Formula(Ib), Formula (II), Formula (IIa), or Formula (IIb) (hereinaftercompounds of Formula (I), (Ia), (Ib), (II), (IIa), or (IIb)),pharmaceutical compositions comprising said compounds, and methods ofuse thereof, for preventing or treating sensory hair cell death andresulting hearing loss (ototoxicity) and loss of balance(vestibulotoxicity). In one aspect, compounds of Formula (I), (Ia),(Ib), (II), (IIa), or (IIb) prevent sensory hair cell death. In anotheraspect, compounds of Formula (I), (Ia), (Ib), (II), (IIa), or (IIb)treat sensory hair cell death. In another aspect, compounds of Formula(I), (Ia), (Ib), (II), (IIa), or (IIb) prevent hearing loss. In anotheraspect, compounds of Formula (I), (Ia), (Ib), (II), (IIa), or (IIb)treat hearing loss. In another aspect compounds of Formula (I), (Ia),(Ib), (II), (IIa), or (IIb) protect against kidney damage in anindividual receiving an aminoglycoside antibiotic.

In another aspect, provided herein is a compound of Formula (I):

wherein:Z is a single bond, double bond, —CH₂—, or —O—;R₁ is aryl or heteroaryl, wherein aryl and heteroaryl are optionallysubstituted with one or more R₄;R₂ is H, C₁-C₆alkyl, —C₁-C₆alkyl-OR₆, —C₁-C₆alkylC₃-C₆cycloalkyl,—C₁-C₆alkylC₂-C₇heterocycloalkyl, —C₁-C₆alkyl-CO₂R₆, optionallysubstituted —C₁-C₆alkylaryl, or optionally substituted—C₁-C₆alkylheteroaryl;R₃ and R₅ are each independently H, or C₁-C₆alkyl; orR₃ and R₅ together form an optionally substituted C₃-C₆cycloalkyl ring,optionally substituted C₂-C₇heterocycloalkyl ring, optionallysubstituted aryl ring, or an optionally substituted heteroaryl ring;each R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀,—N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₇heterocycloalkyl, aryl, andheteroaryl;R₆ is H, or C₁-C₆alkyl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, —C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl;R₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,-heteroaryl, —C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl;R₁₁ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, aryl, -heteroaryl, —C₁-C₆alkylC₃-C₆cycloalkyl,—C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl;R₁₂ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, -aryl, heteroaryl, —C₁-C₆alkylC₃-C₆cycloalkyl,—C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl; or R₁₁ and R₁₂ together withthe nitrogen to which they are attached form an optionally substitutedC₂-C₇heterocycloalkyl ring; andR₁₃ and R₁₄ are each independently H, or C₁-C₆alkyl;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In some embodiments is a compound of Formula (I) or a pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate or hydrate,pharmaceutically acceptable salt hydrate, or pharmaceutically acceptableprodrug thereof, having the structure of Formula (Ia):

In some embodiments is a compound of Formula (I) or a pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate or hydrate,pharmaceutically acceptable salt hydrate, or pharmaceutically acceptableprodrug thereof, having the structure of Formula (Ib):

In another embodiment is a compound of Formula (I), (Ia), or (Ib)wherein R₁ is aryl optionally substituted with one or more R₄. Inanother embodiment is a compound of Formula (I), (Ia), or (Ib) whereinR₁ is phenyl optionally substituted with one or more R₄. In anotherembodiment is a compound of Formula (I), (Ia), or (Ib) wherein R₁ isphenyl substituted with one or more R₄, wherein each R₄ is independentlyselected from F, Cl, Br, I, —CN, —NO₂, —CF₃, —OR₉, —OCF₃, —NR₈R₉,—C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl. In another embodimentis a compound of Formula (I), (Ia), or (Ib) wherein R₁ is phenylsubstituted with one or more R₄, wherein each R₄ is independentlyselected F, Cl, Br, I, —CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, andC₁-C₆alkyl. In another embodiment is a compound of Formula (I), (Ia), or(Ib) wherein R₁ is 4-chlorophenyl. In another embodiment is a compoundof Formula (I), (Ia), or (Ib) wherein R₁₁ and R₁₂ are each H. In anotherembodiment is a compound of Formula (I), (Ia), or (Ib) wherein R₂ is H.In another embodiment is a compound of Formula (I), (Ia), or (Ib)wherein R₂ is C₁-C₆alkyl. In a further embodiment is a compound ofFormula (I), (Ia), or (Ib) wherein R₂ is —CH₃. In another embodiment isa compound of Formula (I), (Ia), or (Ib) wherein R₁₃ and R₁₄ are each H.In another embodiment is a compound of Formula (I), (Ia), or (Ib)wherein R₁₃ and R₁₄ are each —CH₃. In another embodiment is a compoundof Formula (I), (Ia), or (Ib) wherein R₃ and R₅ are each H. In anotherembodiment is a compound of Formula (I), (Ia), or (Ib) wherein Z is asingle bond.

In another aspect, provided herein is a compound of Formula (II):

wherein:X⁻ is a counterion;Z is a single bond, double bond, —CH₂—, or —O—;R₁ is aryl or heteroaryl, wherein aryl and heteroaryl are optionallysubstituted with one or more R₄;R_(2a) is C₁-C₆alkyl, —C₁-C₆alkyl-OR₅, or —C₁-C₆alkylC₃-C₆cycloalkyl;R₂ is C₁-C₆alkyl, —C₁-C₆alkyl-OR₆, —C₁-C₆alkylC₃-C₆cycloalkyl, or—C₁-C₆alkyl-CO₂R₆;R₃ and R₅ are each independently H, or C₁-C₆alkyl; orR₃ and R₅ together form an optionally substituted C₃-C₆cycloalkyl ring,optionally substituted C₂-C₇heterocycloalkyl ring, optionallysubstituted aryl ring, or an optionally substituted heteroaryl ring;each R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀,—N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₇heterocycloalkyl, aryl, andheteroaryl;R₆ is H, or C₁-C₆alkyl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, —C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl;R₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, —C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl;R₁₁ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, aryl, heteroaryl, —C₁-C₆alkylC₃-C₆cycloalkyl,—C₁-C₆alkylaryl, or —C₁i-C₆alkylheteroaryl;R₁₂ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, aryl, heteroaryl, —C₁-C₆alkylC₃-C₆cycloalkyl,—C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl; or R₁₁ and R₁₂ together withthe nitrogen to which they are attached form an optionally substitutedC₂-C₇heterocycloalkyl ring; and R₁₃ and R₁₄ are each independently H, orC₁-C₆alkyl;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In some embodiments is a compound of Formula (I) or a pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate or hydrate,pharmaceutically acceptable salt hydrate, or pharmaceutically acceptableprodrug thereof, having the structure of Formula (IIa):

In some embodiments is a compound of Formula (I) or a pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate or hydrate,pharmaceutically acceptable salt hydrate, or pharmaceutically acceptableprodrug thereof, having the structure of Formula (IIb):

In another embodiment is a compound of Formula (II), (IIa), or (IIb)wherein R₁ is aryl optionally substituted with one or more R₄. Inanother embodiment is a compound of Formula (II), (IIa), or (IIb)wherein R₁ is phenyl optionally substituted with one or more R₄. Inanother embodiment is a compound of Formula (II), (IIa), or (IIb)wherein R₁ is phenyl substituted with one or more R₄, wherein each R₄ isindependently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃, —OR₉, —OCF₃,—NR₈R₉, —C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl. In anotherembodiment is a compound of Formula (II), (IIa), or (IIb) wherein R₁ isphenyl substituted with one or more R₄, wherein each R₄ is independentlyselected F, Cl, Br, I, —CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, andC₁-C₆alkyl. In another embodiment is a compound of Formula (II), (IIa),or (IIb) wherein R₁ is 4-chlorophenyl. In another embodiment is acompound of Formula (II), (IIa), or (IIb) wherein R₁₁ and R₁₂ are eachH. In another embodiment is a compound of Formula (II), (IIa), or (IIb)wherein R₂ is —C₁-C₆alkyl-CO₂R₆. In another embodiment is a compound ofFormula (II), (IIa), or (IIb) wherein R₂ is C₁-C₆alkyl. In a furtherembodiment is a compound of Formula (II), (IIa), or (IIb) wherein R_(2a)is C₁-C₆alkyl. In another embodiment is a compound of Formula (II),(IIa), or (IIb) wherein R₁₃ and R₁₄ are each H. In another embodiment isa compound of Formula (II), (IIa), or (IIb) wherein R₁₃ and R₁₄ are each—CH₃. In another embodiment is a compound of Formula (II), (IIa), or(IIb) wherein R₃ and R₅ are each H. In another embodiment is a compoundof Formula (II), (IIa), or (IIb) wherein Z is a single bond.

In another aspect is a pharmaceutical composition comprising a compoundof Formula (I), (Ia), (Ib), (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate or hydrate,pharmaceutically acceptable salt hydrate, or pharmaceutically acceptableprodrug thereof, and a pharmaceutically acceptable excipient. In anotherembodiment is a pharmaceutical composition comprising a compound ofFormula (I), (Ia), (Ib), (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate or hydrate,pharmaceutically acceptable salt hydrate, or pharmaceutically acceptableprodrug thereof, and a pharmaceutically acceptable excipient furthercomprising an aminoglycoside antibiotic. In another embodiment is apharmaceutical composition comprising a compound of Formula (I), (Ia),(Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,and a pharmaceutically acceptable excipient further comprising anaminoglycoside antibiotic wherein the aminoglycoside antibiotic isselected from streptomycin, neomycin, framycetin, paromomycin,paromomycin sulfate, ribostamycin, kanamycin, amikacin, arbekacin,bekanamycin, dibekacin, tobramycin, spectinomycin, hygromycin B,gentamicin, netilmicin, sisomicin, isepamicin, verdamicin, andastromicin. In some embodiments is a pharmaceutical compositioncomprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), or (IIb),or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof, and a pharmaceuticallyacceptable excipient further comprising an aminoglycoside antibioticwherein the aminoglycoside antibiotic is streptomycin. In someembodiments is a pharmaceutical composition comprising a compound ofFormula (I), (Ia), (Ib), (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate or hydrate,pharmaceutically acceptable salt hydrate, or pharmaceutically acceptableprodrug thereof, and a pharmaceutically acceptable excipient furthercomprising an aminoglycoside antibiotic wherein the aminoglycosideantibiotic is neomycin. In some embodiments is a pharmaceuticalcomposition comprising a compound of Formula (I), (Ia), (Ib), (II),(IIa), or (IIb), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate or hydrate, pharmaceutically acceptable salt hydrate,or pharmaceutically acceptable prodrug thereof, and a pharmaceuticallyacceptable excipient further comprising an aminoglycoside antibioticwherein the aminoglycoside antibiotic is amikacin. In some embodimentsis a pharmaceutical composition comprising a compound of Formula (I),(Ia), (Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptablesalt, pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,and a pharmaceutically acceptable excipient further comprising anaminoglycoside antibiotic wherein the aminoglycoside antibiotic isgentamicin. In some embodiments is a pharmaceutical compositioncomprising a compound of Formula (I), (Ia), (Ib), (II), (IIa), or (IIb),or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof, and a pharmaceuticallyacceptable excipient further comprising an aminoglycoside antibioticwherein the aminoglycoside antibiotic is kanamycin. In some embodimentsis a pharmaceutical composition comprising a compound of Formula (I),(Ia), (Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptablesalt, pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,and a pharmaceutically acceptable excipient further comprising anaminoglycoside antibiotic wherein the aminoglycoside antibiotic istobramycin. In another embodiment of the aforementioned embodiments is apharmaceutical composition formulated for oral, intravenous,intramuscular, or subcutaneous administration.

In another aspect is a method for preventing or treating sensory haircell death in an individual comprising administering to the individual atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof.In another embodiment is a method for preventing or treating sensoryhair cell death in an individual comprising administering to theindividual a therapeutically effective amount of a compound of Formula(I), (Ia), (Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptablesalt, pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,wherein the sensory hair cell death is associated with exposure to anototoxic agent. In another embodiment is a method for preventing ortreating sensory hair cell death in an individual comprisingadministering to the individual a therapeutically effective amount of acompound of Formula (I), (Ia), (Ib), (II), (IIa), or (IIb), or apharmaceutically acceptable salt, pharmaceutically acceptable solvate orhydrate, pharmaceutically acceptable salt hydrate, or pharmaceuticallyacceptable prodrug thereof, wherein the sensory hair cell death isassociated with exposure to an ototoxic agent and the ototoxic agent isan aminoglycoside antibiotic, chemotherapeutic agent, loop diuretic,antimalarial sesquiterpene lactone endoperoxide, antimalarial quinine,salicylate, or interferon polypeptide. In another embodiment is a methodfor preventing or treating sensory hair cell death in an individualcomprising administering to the individual a therapeutically effectiveamount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), or (IIb),or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof, wherein the sensory haircell death is associated with exposure to an aminoglycoside antibiotic.In another embodiment is a method for preventing or treating sensoryhair cell death in an individual comprising administering to theindividual a therapeutically effective amount of a compound of Formula(I), (Ia), (Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptablesalt, pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,wherein the sensory hair cell death is associated with exposure to anaminoglycoside antibiotic and the aminoglycoside antibiotic is selectedfrom streptomycin, neomycin, framycetin, paromomycin, paromomycinsulfate, ribostamycin, kanamycin, amikacin, arbekacin, bekanamycin,dibekacin, tobramycin, spectinomycin, hygromycin B, gentamicin,netilmicin, sisomicin, isepamicin, verdamicin, and astromicin. Inanother embodiment is a method for preventing or treating sensory haircell death in an individual comprising administering to the individual atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,wherein the sensory hair cell death is associated with exposure tostreptomycin. In another embodiment is a method for preventing ortreating sensory hair cell death in an individual comprisingadministering to the individual a therapeutically effective amount of acompound of Formula (I), (Ia), (Ib), (II), (IIa), or (IIb), or apharmaceutically acceptable salt, pharmaceutically acceptable solvate orhydrate, pharmaceutically acceptable salt hydrate, or pharmaceuticallyacceptable prodrug thereof, wherein the sensory hair cell death isassociated with exposure to neomycin. In another embodiment is a methodfor preventing or treating sensory hair cell death in an individualcomprising administering to the individual a therapeutically effectiveamount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), or (IIb),or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof, wherein the sensory haircell death is associated with exposure to amikacin. In anotherembodiment is a method for preventing or treating sensory hair celldeath in an individual comprising administering to the individual atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,wherein the sensory hair cell death is associated with exposure togentamicin. In another embodiment is a method for preventing or treatingsensory hair cell death in an individual comprising administering to theindividual a therapeutically effective amount of a compound of Formula(I), (Ia), (Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptablesalt, pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,wherein the sensory hair cell death is associated with exposure tokanamycin. In another embodiment is a method for preventing or treatingsensory hair cell death in an individual comprising administering to theindividual a therapeutically effective amount of a compound of Formula(I), (Ia), (Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptablesalt, pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,wherein the sensory hair cell death is associated with exposure totobramycin. In another embodiment is a method for preventing or treatingsensory hair cell death in an individual comprising administering to theindividual a therapeutically effective amount of a compound of Formula(I), (Ia), (Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptablesalt, pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,wherein the sensory hair cell death is associated with exposure to achemotherapeutic agent. In another embodiment is a method for preventingor treating sensory hair cell death in an individual comprisingadministering to the individual a therapeutically effective amount of acompound of Formula (I), (Ia), (Ib), (II), (IIa), or (IIb), or apharmaceutically acceptable salt, pharmaceutically acceptable solvate orhydrate, pharmaceutically acceptable salt hydrate, or pharmaceuticallyacceptable prodrug thereof, wherein the sensory hair cell death isassociated with exposure to a chemotherapeutic agent and thechemotherapeutic agent is selected from cisplatin or carboplatin.

In another aspect is a method for preventing or treating hearing loss inan individual comprising administering to the individual atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof.In another embodiment is a method for preventing or treating hearingloss in an individual comprising administering to the individual atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,wherein the hearing loss is associated with exposure to an ototoxicagent. In another embodiment is a method for preventing or treatinghearing loss in an individual comprising administering to the individuala therapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,wherein the hearing loss is associated with exposure to an ototoxicagent and the ototoxic agent is an aminoglycoside antibiotic,chemotherapeutic agent, loop diuretic, antimalarial sesquiterpenelactone endoperoxide, antimalarial quinine, salicylate, or interferonpolypeptide. In another embodiment is a method for preventing ortreating hearing loss in an individual comprising administering to theindividual a therapeutically effective amount of a compound of Formula(I), (Ia), (Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptablesalt, pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,wherein the hearing loss is associated with exposure to anaminoglycoside antibiotic. In another embodiment is a method forpreventing or treating hearing loss in an individual comprisingadministering to the individual a therapeutically effective amount of acompound of Formula (I), (Ia), (Ib), (II), (IIa), or (IIb), or apharmaceutically acceptable salt, pharmaceutically acceptable solvate orhydrate, pharmaceutically acceptable salt hydrate, or pharmaceuticallyacceptable prodrug thereof, wherein the hearing loss is associated withexposure to an aminoglycoside antibiotic and the aminoglycosideantibiotic is selected from streptomycin, neomycin, framycetin,paromomycin, paromomycin sulfate, ribostamycin, kanamycin, amikacin,arbekacin, bekanamycin, dibekacin, tobramycin, spectinomycin, hygromycinB, gentamicin, netilmicin, sisomicin, isepamicin, verdamicin, andastromicin. In another embodiment is a method for preventing or treatinghearing loss in an individual comprising administering to the individuala therapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,wherein the hearing loss is associated with exposure to streptomycin. Inanother embodiment is a method for preventing or treating hearing lossin an individual comprising administering to the individual atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,wherein the hearing loss is associated with exposure to neomycin. Inanother embodiment is a method for preventing or treating hearing lossin an individual comprising administering to the individual atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,wherein the hearing loss is associated with exposure to amikacin. Inanother embodiment is a method for preventing or treating hearing lossin an individual comprising administering to the individual atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,wherein the hearing loss is associated with exposure to gentamicin. Inanother embodiment is a method for preventing or treating hearing lossin an individual comprising administering to the individual atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,wherein the hearing loss is associated with exposure to kanamycin. Inanother embodiment is a method for preventing or treating hearing lossin an individual comprising administering to the individual atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,wherein the hearing loss is associated with exposure to tobramycin. Inanother embodiment is a method for preventing or treating hearing lossin an individual comprising administering to the individual atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,wherein the hearing loss is associated with exposure to achemotherapeutic agent. In another embodiment is a method for preventingor treating hearing loss in an individual comprising administering tothe individual a therapeutically effective amount of a compound ofFormula (I), (Ia), (Ib), (II), (IIa), or (IIb), or a pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate or hydrate,pharmaceutically acceptable salt hydrate, or pharmaceutically acceptableprodrug thereof, wherein the hearing loss is associated with exposure toa chemotherapeutic agent and the chemotherapeutic agent is selected fromcisplatin or carboplatin.

In another embodiment is a method for protecting against kidney damagein an individual receiving an aminoglycoside antibiotic comprisingadministering to the individual a therapeutically effective amount of acompound of Formula (I), (Ia), (Ib), (II), (IIa), or (IIb), or apharmaceutically acceptable salt, pharmaceutically acceptable solvate orhydrate, pharmaceutically acceptable salt hydrate, or pharmaceuticallyacceptable prodrug thereof. In another embodiment is a method forprotecting against kidney damage in an individual receiving anaminoglycoside antibiotic comprising administering to the individual atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,wherein the aminoglycoside antibiotic is selected from streptomycin,neomycin, framycetin, paromomycin, paromomycin sulfate, ribostamycin,kanamycin, amikacin, arbekacin, bekanamycin, dibekacin, tobramycin,spectinomycin, hygromycin B, gentamicin, netilmicin, sisomicin,isepamicin, verdamicin, and astromicin. In another embodiment is amethod for protecting against kidney damage in an individual receivingan aminoglycoside antibiotic comprising administering to the individuala therapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,wherein the aminoglycoside antibiotic is streptomycin. In anotherembodiment is a method for protecting against kidney damage in anindividual receiving an aminoglycoside antibiotic comprisingadministering to the individual a therapeutically effective amount of acompound of Formula (I), (Ia), (Ib), (II), (IIa), or (IIb), or apharmaceutically acceptable salt, pharmaceutically acceptable solvate orhydrate, pharmaceutically acceptable salt hydrate, or pharmaceuticallyacceptable prodrug thereof, wherein the aminoglycoside antibiotic isneomycin. In another embodiment is a method for protecting againstkidney damage in an individual receiving an aminoglycoside antibioticcomprising administering to the individual a therapeutically effectiveamount of a compound of Formula (I), (Ia), (Ib), (II), (IIa), or (IIb),or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof, wherein the aminoglycosideantibiotic is amikacin. In another embodiment is a method for protectingagainst kidney damage in an individual receiving an aminoglycosideantibiotic comprising administering to the individual a therapeuticallyeffective amount of a compound of Formula (I), (Ia), (Ib), (II), (IIa),or (IIb), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate or hydrate, pharmaceutically acceptable salt hydrate,or pharmaceutically acceptable prodrug thereof, wherein theaminoglycoside antibiotic is gentamicin. In another embodiment is amethod for protecting against kidney damage in an individual receivingan aminoglycoside antibiotic comprising administering to the individuala therapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,wherein the aminoglycoside antibiotic is kanamycin. In anotherembodiment is a method for protecting against kidney damage in anindividual receiving an aminoglycoside antibiotic administering to theindividual a therapeutically effective amount of a compound of Formula(I), (Ia), (Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptablesalt, pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,wherein the aminoglycoside antibiotic is tobramycin.

In another aspect is a compound of Formula (I), (Ia), (Ib), (II), (IIa),or (IIb), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate or hydrate, pharmaceutically acceptable salt hydrate,or pharmaceutically acceptable prodrug thereof, with a maximum hair cellprotection of greater than 50% in the assay described in Example 12.

In another aspect is the use of the assay described in Example 12 forthe testing of a compound of Formula (I), (Ia), (Ib), (II), (IIa), or(IIb), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate or hydrate, pharmaceutically acceptable salt hydrate,or pharmaceutically acceptable prodrug thereof.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the effect in the zebrafish hair cell toxicity assayfollowing treatment with cisplatin plus compound 9.

FIG. 2 shows high frequency hearing loss in rats following treatmentwith amikacin alone or amikacin plus compound 9.

FIG. 3 shows creatinine clearance in rats following treatment withamikacin alone or amikacin plus compound 9.

FIG. 4 shows histopathology data in rat kidney following treatment withamikacin alone or amikacin plus compound 9.

DETAILED DESCRIPTION OF THE INVENTION

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an agent” includesa plurality of such agents, and reference to “the cell” includesreference to one or more cells (or to a plurality of cells) andequivalents thereof. When ranges are used herein for physicalproperties, such as molecular weight, or chemical properties, such aschemical formulae, all combinations and subcombinations of ranges andspecific embodiments therein are intended to be included. The term“about” when referring to a number or a numerical range means that thenumber or numerical range referred to is an approximation withinexperimental variability (or within statistical experimental error), andthus the number or numerical range may vary between 1% and 15% of thestated number or numerical range. The term “comprising” (and relatedterms such as “comprise” or “comprises” or “having” or “including”) isnot intended to exclude that in other certain embodiments, for example,an embodiment of any composition of matter, composition, method, orprocess, or the like, described herein, may “consist of” or “consistessentially of” the described features.

Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated below.

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Imino” refers to the ═N—H radical.

“Oximo” refers to the ═N—OH radical.

“Hydrazino” refers to the ═N—NH₂ radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to fifteen carbon atoms (e.g., C₁-C₁₅alkyl). In certain embodiments, an alkyl comprises one to thirteencarbon atoms (e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkylcomprises one to eight carbon atoms (e.g., C₁-C₈ alkyl). In otherembodiments, an alkyl comprises one to six carbon atoms (e.g., C₁-C₆alkyl). In other embodiments, an alkyl comprises one to five carbonatoms (e.g., C₁-C₅ alkyl). In other embodiments, an alkyl comprises oneto four carbon atoms (e.g., C₁-C₄ alkyl). In other embodiments, an alkylcomprises one to three carbon atoms (e.g., C₁-C₃ alkyl). In otherembodiments, an alkyl comprises one to two carbon atoms (e.g., C₁-C₂alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g.,C₁ alkyl). In other embodiments, an alkyl comprises five to fifteencarbon atoms (e.g., C₅-C₁₅ alkyl). In other embodiments, an alkylcomprises five to eight carbon atoms (e.g., C₅-C₈ alkyl). In otherembodiments, an alkyl comprises two to six carbon atoms (e.g., C₂-C₆alkyl). In other embodiments, an alkyl comprises two to five carbonatoms (e.g., C₂-C₅ alkyl). In other embodiments, an alkyl comprisesthree to five carbon atoms (e.g., C₃-C₅ alkyl). In other embodiments,the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl),1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl(sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl),1-pentyl (n-pentyl). Unless stated otherwise specifically in thespecification, an alkyl group is optionally substituted by one or moreof the following substituents: halo, cyano, nitro, oxo, thioxo, imino,oximo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl orheteroarylalkyl. Depending on the structure, an alkyl group isoptionally a monoradical or a diradical (i.e. an alkylene group).

“Alkoxy” refers to a radical bonded through an oxygen atom of theformula —O-alkyl, where alkyl is an alkyl chain as defined above.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon double bond, and having from two to twelvecarbon atoms. In certain embodiments, an alkenyl comprises two to eightcarbon atoms. In other embodiments, an alkenyl comprises two to sixcarbon atoms. In other embodiments, an alkenyl comprises two to fourcarbon atoms. The alkenyl is attached to the rest of the molecule by asingle bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e.,allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unlessstated otherwise specifically in the specification, an alkenyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂,—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl orheteroarylalkyl.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon triple bond, having from two to twelve carbonatoms. In certain embodiments, an alkynyl comprises two to eight carbonatoms. In other embodiments, an alkynyl has two to four carbon atoms.The alkynyl is attached to the rest of the molecule by a single bond,for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and thelike. Unless stated otherwise specifically in the specification, analkynyl group is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is1 or 2), —S(O)_(t)OR^(a)(where t is 1 or 2), —S(O)_(t)R^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl orheteroarylalkyl.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, for example, methylene,ethylene, propylene, n-butylene, and the like. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkylene chain to the rest of the molecule and to the radical group isoptionally through one carbon in the alkylene chain or through any twocarbons within the chain. In certain embodiments, an alkylene comprisesone to eight carbon atoms (e.g., C₁-C₈ alkylene). In other embodiments,an alkylene comprises one to five carbon atoms (e.g., C₁-C₅ alkylene).In other embodiments, an alkylene comprises one to four carbon atoms(e.g., C₁-C₄ alkylene). In other embodiments, an alkylene comprises oneto three carbon atoms (e.g., C₁-C₃ alkylene). In other embodiments, analkylene comprises one to two carbon atoms (e.g., C₁-C₂ alkylene). Inother embodiments, an alkylene comprises one carbon atom (e.g., C₁alkylene). In other embodiments, an alkylene comprises five to eightcarbon atoms (e.g., C₅-C₅ alkylene). In other embodiments, an alkylenecomprises two to five carbon atoms (e.g., C₂-C₅ alkylene). In otherembodiments, an alkylene comprises three to five carbon atoms (e.g.,C₃-C₅ alkylene). Unless stated otherwise specifically in thespecification, an alkylene chain is optionally substituted by one ormore of the following substituents: halo, cyano, nitro, oxo, thioxo,imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Aryl” refers to a radical derived from an aromatic monocyclic ormulticyclic hydrocarbon ring system by removing a hydrogen atom from aring carbon atom. The aromatic monocyclic or multicyclic hydrocarbonring system contains only hydrogen and carbon from five to eighteencarbon atoms, where at least one of the rings in the ring system isfully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system in accordance with the Hückel theory. The ring systemfrom which aryl groups are derived include, but are not limited to,groups such as benzene, fluorene, indane, indene, tetralin andnaphthalene. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals optionally substituted by one or more substituentsindependently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocycloalkyl, optionallysubstituted heterocycloalkylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl (optionally substituted with one or more halo groups), aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,each R^(b) is independently a direct bond or a straight or branchedalkylene or alkenylene chain, and R^(c) is a straight or branchedalkylene or alkenylene chain, and where each of the above substituentsis unsubstituted unless otherwise indicated.

“Aralkyl” refers to a radical of the formula —R^(c)-aryl where R^(c) isan alkylene chain as defined above, for example, methylene, ethylene,and the like. The alkylene chain part of the aralkyl radical isoptionally substituted as described above for an alkylene chain. Thearyl part of the aralkyl radical is optionally substituted as describedabove for an aryl group.

“Aralkenyl” refers to a radical of the formula —R^(d)-aryl where R^(d)is an alkenylene chain as defined above. The aryl part of the aralkenylradical is optionally substituted as described above for an aryl group.The alkenylene chain part of the aralkenyl radical is optionallysubstituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —R^(e)-aryl, where R^(e)is an alkynylene chain as defined above. The aryl part of the aralkynylradical is optionally substituted as described above for an aryl group.The alkynylene chain part of the aralkynyl radical is optionallysubstituted as defined above for an alkynylene chain.

“Aralkoxy” refers to a radical bonded through an oxygen atom of theformula —O—R^(c)-aryl where R^(c) is an alkylene chain as defined above,for example, methylene, ethylene, and the like. The alkylene chain partof the aralkyl radical is optionally substituted as described above foran alkylene chain. The aryl part of the aralkyl radical is optionallysubstituted as described above for an aryl group.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which may include fused or bridged ring systems, having from three tofifteen carbon atoms. In certain embodiments, a cycloalkyl comprisesthree to ten carbon atoms. In other embodiments, a cycloalkyl comprisesfive to seven carbon atoms. The cycloalkyl is attached to the rest ofthe molecule by a single bond. Cycloalkyl may be saturated, (i.e.,containing single C—C bonds only) or partially unsaturated. Examples ofmonocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturatedcycloalkyl is also referred to as “cycloalkenyl.” Examples of monocycliccycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl,and cyclooctenyl. Polycyclic cycloalkyl radicals include, for example,adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl,decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unlessotherwise stated specifically in the specification, the term“cycloalkyl” is meant to include cycloalkyl radicals that are optionallysubstituted by one or more substituents independently selected fromalkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted aralkenyl, optionally substituted aralkynyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocycloalkyl, optionally substitutedheterocycloalkylalkyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a),—R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂,—R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂,—R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each R^(b) isindependently a direct bond or a straight or branched alkylene oralkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain, and where each of the above substituents isunsubstituted unless otherwise indicated.

“Cycloalkylalkyl” refers to a radical of the formula —R^(c)-cycloalkylwhere R^(c) is an alkylene chain as defined above. The alkylene chainand the cycloalkyl radical is optionally substituted as defined above.

“Cycloalkylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-cycloalkyl where R^(c) is an alkylene chain asdefined above. The alkylene chain and the cycloalkyl radical isoptionally substituted as defined above.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodosubstituents.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, fluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Thealkyl part of the fluoroalkyl radical may be optionally substituted asdefined above for an alkyl group.

“Heterocycloalkyl” refers to a stable 3- to 18-membered non-aromaticring radical that comprises two to twelve carbon atoms and from one tosix heteroatoms selected from nitrogen, oxygen and sulfur. Unless statedotherwise specifically in the specification, the heterocycloalkylradical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system,which may include fused or bridged ring systems. The heteroatoms in theheterocycloalkyl radical may be optionally oxidized. One or morenitrogen atoms, if present, are optionally quaternized. Theheterocycloalkyl radical is partially or fully saturated. Theheterocycloalkyl may be attached to the rest of the molecule through anyatom of the ring(s). Examples of such heterocycloalkyl radicals include,but are not limited to, dioxolanyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl,tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless statedotherwise specifically in the specification, the term “heterocycloalkyl”is meant to include heterocycloalkyl radicals as defined above that areoptionally substituted by one or more substituents selected from alkyl,alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted aralkenyl, optionally substituted aralkynyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocycloalkyl, optionally substitutedheterocycloalkylalkyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a),—R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂,—R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂,—R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each R^(b) isindependently a direct bond or a straight or branched alkylene oralkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain, and where each of the above substituents isunsubstituted unless otherwise indicated.

“N-heterocycloalkyl” or “N-attached heterocycloalkyl” refers to aheterocycloalkyl radical as defined above containing at least onenitrogen and where the point of attachment of the heterocycloalkylradical to the rest of the molecule is through a nitrogen atom in theheterocycloalkyl radical. An N-heterocycloalkyl radical is optionallysubstituted as described above for heterocycloalkyl radicals. Examplesof such N-heterocycloalkyl radicals include, but are not limited to,1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl,pyrazolidinyl, imidazolinyl, and imidazolidinyl.

“C-heterocycloalkyl” or “C-attached heterocycloalkyl” refers to aheterocycloalkyl radical as defined above containing at least oneheteroatom and where the point of attachment of the heterocycloalkylradical to the rest of the molecule is through a carbon atom in theheterocycloalkyl radical. A C-heterocycloalkyl radical is optionallysubstituted as described above for heterocycloalkyl radicals. Examplesof such C-heterocycloalkyl radicals include, but are not limited to,2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or3-pyrrolidinyl, and the like.

“Heterocycloalkylalkyl” refers to a radical of the formula—R^(c)-heterocycloalkyl where R^(c) is an alkylene chain as definedabove. If the heterocycloalkyl is a nitrogen-containingheterocycloalkyl, the heterocycloalkyl is optionally attached to thealkyl radical at the nitrogen atom. The alkylene chain of theheterocycloalkylalkyl radical is optionally substituted as defined abovefor an alkylene chain. The heterocycloalkyl part of theheterocycloalkylalkyl radical is optionally substituted as defined abovefor a heterocycloalkyl group.

“Heterocycloalkylalkoxy” refers to a radical bonded through an oxygenatom of the formula —O—R^(c)-heterocycloalkyl where R^(c) is an alkylenechain as defined above. If the heterocycloalkyl is a nitrogen-containingheterocycloalkyl, the heterocycloalkyl is optionally attached to thealkyl radical at the nitrogen atom. The alkylene chain of theheterocycloalkylalkoxy radical is optionally substituted as definedabove for an alkylene chain. The heterocycloalkyl part of theheterocycloalkylalkoxy radical is optionally substituted as definedabove for a heterocycloalkyl group.

“Heteroaryl” refers to a radical derived from a 3- to 18-memberedaromatic ring radical that comprises two to seventeen carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen and sulfur.As used herein, the heteroaryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, wherein at least one of the ringsin the ring system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) π-electron system in accordance with the Hückeltheory. Heteroaryl includes fused or bridged ring systems. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s). Examples of heteroaryls include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl,benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, theterm “heteroaryl” is meant to include heteroaryl radicals as definedabove which are optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl,haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocycloalkyl, optionally substituted heterocycloalkylalkyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl orheteroarylalkyl, each R^(b) is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R^(c) is a straight orbranched alkylene or alkenylene chain, and where each of the abovesubstituents is unsubstituted unless otherwise indicated.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R^(c)-heteroaryl,where R^(c) is an alkylene chain as defined above. If the heteroaryl isa nitrogen-containing heteroaryl, the heteroaryl is optionally attachedto the alkyl radical at the nitrogen atom. The alkylene chain of theheteroarylalkyl radical is optionally substituted as defined above foran alkylene chain. The heteroaryl part of the heteroarylalkyl radical isoptionally substituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-heteroaryl, where R^(c) is an alkylene chain asdefined above. If the heteroaryl is a nitrogen-containing heteroaryl,the heteroaryl is optionally attached to the alkyl radical at thenitrogen atom. The alkylene chain of the heteroarylalkoxy radical isoptionally substituted as defined above for an alkylene chain. Theheteroaryl part of the heteroarylalkoxy radical is optionallysubstituted as defined above for a heteroaryl group.

The compounds disclosed herein may contain one or more asymmetriccenters and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-. Unless stated otherwise, it isintended that all stereoisomeric forms of the compounds disclosed hereinare contemplated by this disclosure. When the compounds described hereincontain alkene double bonds, and unless specified otherwise, it isintended that this disclosure includes both E and Z geometric isomers(e.g., cis or trans.) Likewise, all possible isomers, as well as theirracemic and optically pure forms, and all tautomeric forms are alsointended to be included. The term “geometric isomer” refers to E or Zgeometric isomers (e.g., cis or trans) of an alkene double bond. Theterm “positional isomer” refers to structural isomers around a centralring, such as ortho-, meta-, and para-isomers around a benzene ring.

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible. Thecompounds presented herein may, in certain embodiments, exist astautomers. In circumstances where tautomerization is possible, achemical equilibrium of the tautomers will exist. The exact ratio of thetautomers depends on several factors, including physical state,temperature, solvent, and pH. Some examples of tautomeric equilibriuminclude:

“Optional” or “optionally” means that a subsequently described event orcircumstance may or may not occur and that the description includesinstances when the event or circumstance occurs and instances in whichit does not.

“Optionally substituted” or “substituted” means that the referencedgroup may be substituted with one or more additional group(s)individually and independently selected from alkyl, cycloalkyl, aryl,heteroaryl, heterocycloalkyl, —OH, alkoxy, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, —CN, alkyne,C₁-C₆alkylalkyne, halo, acyl, acyloxy, —CO₂H, —CO₂-alkyl, nitro,haloalkyl, fluoroalkyl, and amino, including mono- and di-substitutedamino groups (e.g. —NH₂, —NHR, —N(R)₂), and the protected derivativesthereof. By way of example, an optional substituents may be L^(s)R^(s),wherein each L^(s) is independently selected from a bond, —O—, —C(═O)—,—S—, —S(═O)—, —S(═O)₂—, —NH—, —NHC(O)—, —C(O)NH—, S(═O)₂NH—, —NHS(═O)₂,—OC(O)NH—, —NHC(O)O—, —(C₁-C₆alkyl)-, or —(C₂-C₆alkenyl)-; and eachR^(s) is independently selected from among H, (C₁-C₆alkyl),(C₃-C₈cycloalkyl), aryl, heteroaryl, heterocycloalkyl, andC₁-C₆heteroalkyl. The protecting groups that may form the protectivederivatives of the above substituents are found in sources such asGreene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., JohnWiley & Sons, New York, N.Y., 1999, and Kocienski, Protective Groups,Thieme Verlag, New York, N.Y., 1994, which are incorporated herein byreference for such disclosure.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of the compoundsdescribed herein is intended to encompass any and all pharmaceuticallysuitable salt forms. Preferred pharmaceutically acceptable salts of thecompounds described herein are pharmaceutically acceptable acid additionsalts and pharmaceutically acceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,phosphorous acid, and the like. Also included are salts that are formedwith organic acids such as aliphatic mono- and dicarboxylic acids,phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioicacids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. andinclude, for example, acetic acid, trifluoroacetic acid, propionic acid,glycolic acid, pyruvic acid, pyroglutamic acid, oxalic acid, maleicacid, malonic acid, succinic acid, fumaric acid, tartaric acid, citricacid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and thelike. Exemplary salts thus include sulfates, pyrosulfates, bisulfates,sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates,dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides,bromides, iodides, acetates, trifluoroacetates, propionates, caprylates,isobutyrates, oxalates, malonates, succinate suberates, sebacates,fumarates, maleates, mandelates, benzoates, chlorobenzoates,methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates,toluenesulfonates, phenylacetates, citrates, lactates, malates,tartrates, methanesulfonates, and the like. Also contemplated are saltsof amino acids, such as arginates, gluconates, and galacturonates (see,for example, Berge S. M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 66:1-19 (1997), which is hereby incorporated byreference in its entirety). Acid addition salts of basic compounds maybe prepared by contacting the free base forms with a sufficient amountof the desired acid to produce the salt according to known methods andtechniques.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Pharmaceutically acceptable base addition salts may beformed with metals or amines, such as alkali and alkaline earth metalsor organic amines. Salts derived from inorganic bases include, but arenot limited to, sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Salts derived from organic bases include, but are not limited to, saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, for example, isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine,diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline,betaine, ethylenediamine, ethylenedianiline, N-methylglucamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, polyamine resins and the like. See Bergeet al., supra.

“Counterion” refers to an ion that accompanies an ionic species in orderto maintain electric neutrality. Examples of counterions include, butare not limited to, Cl⁻, Br⁻, I⁻, and CF₃CO₂ ⁻.

As used herein, “treatment” or “treating,” or “palliating” or“ameliorating” are used interchangeably herein. These terms refers to anapproach for obtaining beneficial or desired results including but notlimited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forprophylactic benefit, the compositions may be administered to a patientat risk of developing a particular disease, or to a patient reportingone or more of the physiological symptoms of a disease, even though adiagnosis of this disease may not have been made.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein. Thus, the term “prodrug” refers to aprecursor of a biologically active compound that is pharmaceuticallyacceptable. A prodrug may be inactive when administered to a subject,but is converted in vivo to an active compound, for example, byhydrolysis. The prodrug compound often offers advantages of solubility,tissue compatibility or delayed release in a mammalian organism (see,e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier,Amsterdam).

A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugsas Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated in full by reference herein.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound in vivo when such prodrug isadministered to a mammalian subject. Prodrugs of an active compound, asdescribed herein, may be prepared by modifying functional groups presentin the active compound in such a way that the modifications are cleaved,either in routine manipulation or in vivo, to the parent activecompound. Prodrugs include compounds wherein a hydroxy, amino ormercapto group is bonded to any group that, when the prodrug of theactive compound is administered to a mammalian subject, cleaves to forma free hydroxy, free amino or free mercapto group, respectively.Examples of prodrugs include, but are not limited to, acetate, formateand benzoate derivatives of alcohol or amine functional groups in theactive compounds and the like.

Compounds

In some embodiments, the compounds, and compositions comprising thesecompounds, described herein are useful for preventing or treatingsensory hair cell death. In some embodiments, the compounds, andcompositions comprising these compounds, described herein are useful forpreventing or treating hearing loss. In some embodiments, the compounds,and compositions comprising these compounds, described herein are usefulfor protecting against kidney damage in an individual receiving anaminoglycoside antibiotic.

In one embodiment is a compound of Formula (I):

wherein:Z is a single bond, double bond, —CH₂—, or —O—;R₁ is aryl or heteroaryl, wherein aryl and heteroaryl are optionallysubstituted with one or more R₄;R₂ is H, C₁-C₆alkyl, C₁-C₆alkyl-OR₆, C₁-C₆alkylC₃-C₆cycloalkyl,C₁-C₆alkylC₂-C₇heterocycloalkyl, C₁-C₆alkyl-CO₂R₆, optionallysubstituted C₁-C₆alkylaryl, or optionally substitutedC₁-C₆alkylheteroaryl;R₃ and R₅ are each independently H, or C₁-C₆alkyl; orR₃ and R₅ together form an optionally substituted C₃-C₆cycloalkyl ring,optionally substituted C₂-C₇heterocycloalkyl ring, optionallysubstituted aryl ring, or an optionally substituted heteroaryl ring;each R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀,—N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₇heterocycloalkyl, aryl, andheteroaryl;R₆ is H, or C₁-C₆alkyl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, C₁-C₆alkylaryl, or C₁-C₆alkylheteroaryl;R₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, C₁-C₆alkylaryl, or C₁-C₆alkylheteroaryl;R₁₁ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylC₃-C₆cycloalkyl,C₁-C₆alkylaryl, or C₁-C₆alkylheteroaryl;R₁₂ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylC₃-C₆cycloalkyl,C₁-C₆alkylaryl, or C₁-C₆alkylheteroaryl; or R₁₁ and R₁₂ together withthe nitrogen to which they are attached form an optionally substitutedC₂-C₇heterocycloalkyl ring; andR₁₃ and R₁₄ are each independently H, or C₁-C₆alkyl;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In one embodiment is a compound of Formula (I), wherein R₁ is aryloptionally substituted with one or more R₄. In another embodiment is acompound of Formula (I), wherein R₁ is phenyl optionally substitutedwith one or more R₄. In another embodiment is a compound of Formula (I),wherein R₁ is phenyl substituted with one or more R₄, wherein each R₄ isindependently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃, —OR₉, —OCF₃,—NR₈R₉, —C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl. In anotherembodiment is a compound of Formula (I), wherein R₁ is phenylsubstituted with one or more R₄, wherein each R₄ is independentlyselected F, Cl, Br, I, —CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, andC₁-C₆alkyl. In another embodiment is a compound of Formula (I), whereinR₁ is 4-chlorophenyl.

In another embodiment is a compound of Formula (I) wherein R₁ isheteroaryl optionally substituted with one or more R₄. In anotherembodiment is a compound of Formula (I), wherein R₁ is heteroarylsubstituted with one or more R₄, wherein each R₄ is independentlyselected from F, Cl, Br, I, —CN, —NO₂, —CF₃, —OR₉, —OCF₃, —NR₈R₉,—C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl. In another embodimentis a compound of Formula (I), wherein R₁ is heteroaryl substituted withone or more R₄, wherein each R₄ is independently selected F, Cl, Br, I,—CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, and C₁-C₆alkyl. In anotherembodiment is a compound of Formula (I), wherein heteroaryl is pyridyl.

In another embodiment is a compound of Formula (I) wherein R₁₁ and R₁₂are each C₁-C₆alkyl. In another embodiment is a compound of Formula (I)wherein R₁₁ and R₁₂ are each —CH₃. In another embodiment is a compoundof Formula (I) wherein R₁₁ is H and R₁₂ is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (I) wherein R₁₁ is H and R₁₂ is—CH₃. In another embodiment is a compound of Formula (I) wherein R₁₁ isH and R₁₂ is C₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (I) wherein R₁₁ is H and R₁₂ is C₁-C₆alkylC₃-C₆cycloalkyl. Inanother embodiment is a compound of Formula (I) wherein R₁₁ is H and R₁₂is C₁-C₆alkylaryl. In another embodiment is a compound of Formula (I)wherein R₁₁ is H and R₁₂ is C₁-C₆alkylheteroaryl.

In another embodiment is a compound of Formula (I) wherein R₁₃ and R₁₄are each H. In another embodiment is a compound of Formula (I) whereinR₁₃ and R₁₄ are each —CH₃.

In another embodiment is a compound of Formula (I) wherein R₃ and R₅ areeach H. In another embodiment is a compound of Formula (I) wherein R₃and R₅ are each —CH₃.

In another embodiment is a compound of Formula (I) wherein R₁₁ and R₁₂are each H.

In another embodiment is a compound of Formula (I), wherein R₂ is H. Inanother embodiment is a compound of Formula (I), wherein R₂ isC₁-C₆alkyl. In a further embodiment is a compound of Formula (I),wherein R₂ is —CH₃. In another embodiment is a compound of Formula (I),wherein R₂ is —CH₂CH₃. In another embodiment is a compound of Formula(I), wherein R₂ is C₁-C₆alkyl-OR₆. In another embodiment is a compoundof Formula (I), wherein R₂ is C₁-C₆alkyl-OH. In another embodiment is acompound of Formula (I), wherein R₂ is C₁-C₆alkylC₃-C₆cycloalkyl. Inanother embodiment is a compound of Formula (I), wherein R₂ is—CH₂—C₃-C₆cycloalkyl. In another embodiment is a compound of Formula(I), wherein R₂ is —CH₂— cyclopropyl. In another embodiment is acompound of Formula (I), wherein R₂ is —CH₂-cyclobutyl. In anotherembodiment is a compound of Formula (I), wherein R₂ is —CH₂-cyclopentyl.In another embodiment is a compound of Formula (I), wherein R₂ is—CH₂-cyclohexyl. In another embodiment is a compound of Formula (I),wherein R₂ is C₁-C₆alkylC₂-C₇heterocycloalkyl. In another embodiment isa compound of Formula (I), wherein R₂ is —CH₂—C₂-C₇heterocycloalkyl. Inanother embodiment is a compound of Formula (I), wherein R₂ isC₁-C₆alkyl-CO₂R₆. In another embodiment is a compound of Formula (I),wherein R₂ is C₁-C₆alkyl-CO₂CH₃. In another embodiment is a compound ofFormula (I), wherein R₂ is C₁-C₆alkyl-CO₂CH₂CH₃. In another embodimentis a compound of Formula (I), wherein R₂ is optionally substitutedC₁-C₆alkylaryl. In another embodiment is a compound of Formula (I),wherein R₂ is optionally substituted C₁-C₆alkylheteroaryl.

In another embodiment is a compound of Formula (I), wherein Z is asingle bond. In another embodiment is a compound of Formula (I), whereinZ is a double bond. In another embodiment is a compound of Formula (I),wherein Z is —CH₂—. In another embodiment is a compound of Formula (I),wherein Z is —O—.

In another embodiment is a compound of Formula (I), having the structureof Formula (I′):

wherein:R₁ is aryl or heteroaryl, wherein aryl and heteroaryl are optionallysubstituted with one or more R₄;R₂ is H, C₁-C₆alkyl, C₁-C₆alkyl-OR₆, C₁-C₆alkylC₃-C₆cycloalkyl,C₁-C₆alkylC₂-C₇heterocycloalkyl, C₁-C₆alkyl-CO₂R₆, optionallysubstituted C₁-C₆alkylaryl, or optionally substitutedC₁-C₆alkylheteroaryl;each R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀,—N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₇heterocycloalkyl, aryl, andheteroaryl;R₆ is H, or C₁-C₆alkyl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, C₁-C₆alkylaryl, or C₁-C₆alkylheteroaryl; andR₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, C₁-C₆alkylaryl, or C₁-C₆alkylheteroaryl;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In one embodiment is a compound of Formula (I′), wherein R₁ is aryloptionally substituted with one or more R₄. In another embodiment is acompound of Formula (I′), wherein R₁ is phenyl optionally substitutedwith one or more R₄. In another embodiment is a compound of Formula(I′), wherein R₁ is phenyl substituted with one or more R₄, wherein eachR₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃, —OR₉,—OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl. Inanother embodiment is a compound of Formula (I′), wherein R₁ is phenylsubstituted with one or more R₄, wherein each R₄ is independentlyselected F, Cl, Br, I, —CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, andC₁-C₆alkyl. In another embodiment is a compound of Formula (I′), whereinR₁ is 4-chlorophenyl.

In another embodiment is a compound of Formula (I′) wherein R₁ isheteroaryl optionally substituted with one or more R₄. In anotherembodiment is a compound of Formula (I′), wherein R₁ is heteroarylsubstituted with one or more R₄, wherein each R₄ is independentlyselected from F, Cl, Br, I, —CN, —NO₂, —CF₃, —OR₉, —OCF₃, —NR₈R₉,—C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl. In another embodimentis a compound of Formula (I′), wherein R₁ is heteroaryl substituted withone or more R₄, wherein each R₄ is independently selected F, Cl, Br, I,—CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, and C₁-C₆alkyl. In anotherembodiment is a compound of Formula (I′), wherein heteroaryl is pyridyl.

In another embodiment is a compound of Formula (I′), wherein R₂ is H. Inanother embodiment is a compound of Formula (I′), wherein R₂ isC₁-C₆alkyl. In a further embodiment is a compound of Formula (I′),wherein R₂ is —CH₃. In another embodiment is a compound of Formula (I′),wherein R₂ is —CH₂CH₃. In another embodiment is a compound of Formula(I′), wherein R₂ is C₁-C₆alkyl-OR₆. In another embodiment is a compoundof Formula (I′), wherein R₂ is C₁-C₆alkyl-OH. In another embodiment is acompound of Formula (I′), wherein R₂ is C₁-C₆alkylC₃-C₆cycloalkyl. Inanother embodiment is a compound of Formula (I′), wherein R₂ is—CH₂—C₃-C₆cycloalkyl. In another embodiment is a compound of Formula(I′), wherein R₂ is —CH₂— cyclopropyl. In another embodiment is acompound of Formula (I′), wherein R₂ is —CH₂— cyclobutyl. In anotherembodiment is a compound of Formula (I′), wherein R₂ is—CH₂-cyclopentyl. In another embodiment is a compound of Formula (I′),wherein R₂ is —CH₂-cyclohexyl. In another embodiment is a compound ofFormula (I′), wherein R₂ is C₁-C₆alkylC₂-C₇heterocycloalkyl. In anotherembodiment is a compound of Formula (I′), wherein R₂ is—CH₂—C₂-C₇heterocycloalkyl. In another embodiment is a compound ofFormula (I′), wherein R₂ is C₁-C₆alkyl-CO₂R₆. In another embodiment is acompound of Formula (I′), wherein R₂ is C₁-C₆alkyl-CO₂CH₃. In anotherembodiment is a compound of Formula (I′), wherein R₂ isC₁-C₆alkyl-CO₂CH₂CH₃. In another embodiment is a compound of Formula(I′), wherein R₂ is optionally substituted C₁-C₆alkylaryl. In anotherembodiment is a compound of Formula (I′), wherein R₂ is optionallysubstituted C₁-C₆alkylheteroaryl.

In another embodiment is a compound of Formula (I), having the structureof Formula (I″):

wherein:R₂ is H, C₁-C₆alkyl, C₁-C₆alkyl-OR₆, C₁-C₆alkylC₃-C₆cycloalkyl,C₁-C₆alkylC₂-C₇heterocycloalkyl, C₁-C₆alkyl-CO₂R₆, optionallysubstituted C₁-C₆alkylaryl, or optionally substitutedC₁-C₆alkylheteroaryl; andR₆ is H, or C₁-C₆alkyl;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In one embodiment is a compound of Formula (I″), wherein R₂ is H. Inanother embodiment is a compound of Formula (I″), wherein R₂ isC₁-C₆alkyl. In a further embodiment is a compound of Formula (I″),wherein R₂ is —CH₃. In another embodiment is a compound of Formula (I″),wherein R₂ is —CH₂CH₃. In another embodiment is a compound of Formula(I″), wherein R₂ is C₁-C₆alkyl-OR₆. In another embodiment is a compoundof Formula (I″), wherein R₂ is C₁-C₆alkyl-OH. In another embodiment is acompound of Formula (I″), wherein R₂ is C₁-C₆alkylC₃-C₆cycloalkyl. Inanother embodiment is a compound of Formula (I″), wherein R₂ is—CH₂—C₃-C₆cycloalkyl. In another embodiment is a compound of Formula(I″), wherein R₂ is —CH₂— cyclopropyl. In another embodiment is acompound of Formula (I″), wherein R₂ is —CH₂— cyclobutyl. In anotherembodiment is a compound of Formula (I″), wherein R₂ is —CH₂—cyclopentyl. In another embodiment is a compound of Formula (I″),wherein R₂ is —CH₂— cyclohexyl. In another embodiment is a compound ofFormula (I″), wherein R₂ is C₁-C₆alkylC₂-C₇heterocycloalkyl. In anotherembodiment is a compound of Formula (I″), wherein R₂ is—CH₂—C₂-C₇heterocycloalkyl. In another embodiment is a compound ofFormula (I″), wherein R₂ is C₁-C₆alkyl-CO₂R₆. In another embodiment is acompound of Formula (I″), wherein R₂ is C₁-C₆alkyl-CO₂CH₃. In anotherembodiment is a compound of Formula (I″), wherein R₂ isC₁-C₆alkyl-CO₂CH₂CH₃. In another embodiment is a compound of Formula(I″), wherein R₂ is optionally substituted C₁-C₆alkylaryl. In anotherembodiment is a compound of Formula (I″), wherein R₂ is optionallysubstituted C₁-C₆alkylheteroaryl.

In another embodiment is a compound of Formula (Ia):

wherein:Z is a single bond, double bond, —CH₂—, or —O—;R₁ is aryl or heteroaryl, wherein aryl and heteroaryl are optionallysubstituted with one or more R₄;R₂ is H, C₁-C₆alkyl, C₁-C₆alkyl-OR₆, C₁-C₆alkylC₃-C₆cycloalkyl,C₁-C₆alkylC₂-C₇heterocycloalkyl, C₁-C₆alkyl-CO₂R₆, optionallysubstituted C₁-C₆alkylaryl, or optionally substitutedC₁-C₆alkylheteroaryl;R₃ and R₅ are each independently H, or C₁-C₆alkyl; orR₃ and R₅ together form an optionally substituted C₃-C₆cycloalkyl ring,optionally substituted C₂-C₇heterocycloalkyl ring, optionallysubstituted aryl ring, or an optionally substituted heteroaryl ring;each R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀,—N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₇heterocycloalkyl, aryl, andheteroaryl;R₆ is H, or C₁-C₆alkyl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, C₁-C₆alkylaryl, or C₁-C₆alkylheteroaryl;R₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, C₁-C₆alkylaryl, or C₁-C₆alkylheteroaryl;R₁₁ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylC₃-C₆cycloalkyl,C₁-C₆alkylaryl, or C₁-C₆alkylheteroaryl;R₁₂ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylC₃-C₆cycloalkyl,C₁-C₆alkylaryl, or C₁-C₆alkylheteroaryl; or R₁₁ and R₁₂ together withthe nitrogen to which they are attached form an optionally substitutedC₂-C₇heterocycloalkyl ring; andR₁₃ and R₁₄ are each independently H, or C₁-C₆alkyl;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In one embodiment is a compound of Formula (Ia), wherein R₁ is aryloptionally substituted with one or more R₄. In another embodiment is acompound of Formula (Ia), wherein R₁ is phenyl optionally substitutedwith one or more R₄. In another embodiment is a compound of Formula(Ia), wherein R₁ is phenyl substituted with one or more R₄, wherein eachR₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃, —OR₉,—OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl. Inanother embodiment is a compound of Formula (Ia), wherein R₁ is phenylsubstituted with one or more R₄, wherein each R₄ is independentlyselected F, Cl, Br, I, —CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, andC₁-C₆alkyl. In another embodiment is a compound of Formula (Ia), whereinR₁ is 4-chlorophenyl.

In another embodiment is a compound of Formula (Ia) wherein R₁ isheteroaryl optionally substituted with one or more R₄. In anotherembodiment is a compound of Formula (Ia), wherein R₁ is heteroarylsubstituted with one or more R₄, wherein each R₄ is independentlyselected from F, Cl, Br, I, —CN, —NO₂, —CF₃, —OR₉, —OCF₃, —NR₈R₉,—C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl. In another embodimentis a compound of Formula (Ia), wherein R₁ is heteroaryl substituted withone or more R₄, wherein each R₄ is independently selected F, Cl, Br, I,—CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, and C₁-C₆alkyl. In anotherembodiment is a compound of Formula (Ia), wherein heteroaryl is pyridyl.

In another embodiment is a compound of Formula (Ia) wherein R₁₁ and R₁₂are each C₁-C₆alkyl. In another embodiment is a compound of Formula (Ia)wherein R₁₁ and R₁₂ are each —CH₃. In another embodiment is a compoundof Formula (Ia) wherein R₁₁ is H and R₁₂ is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (Ia) wherein R₁₁ is H and R₁₂ is—CH₃. In another embodiment is a compound of Formula (Ia) wherein R₁₁ isH and R₁₂ is C₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (Ia) wherein R₁₁ is H and R₁₂ is C₁-C₆alkylC₃-C₆cycloalkyl. Inanother embodiment is a compound of Formula (Ia) wherein R₁₁ is H andR₁₂ is C₁-C₆alkylaryl. In another embodiment is a compound of Formula(Ia) wherein R₁₁ is H and R₁₂ is C₁-C₆alkylheteroaryl.

In another embodiment is a compound of Formula (Ia) wherein R₁₃ and R₁₄are each H. In another embodiment is a compound of Formula (Ia) whereinR₁₃ and R₁₄ are each —CH₃.

In another embodiment is a compound of Formula (Ia) wherein R₃ and R₅are each H. In another embodiment is a compound of Formula (Ia) whereinR₃ and R₅ are each —CH₃.

In another embodiment is a compound of Formula (Ia) wherein R₁₁ and R₁₂are each H.

In another embodiment is a compound of Formula (Ia), wherein R₂ is H. Inanother embodiment is a compound of Formula (Ia), wherein R₂ isC₁-C₆alkyl. In a further embodiment is a compound of Formula (Ia),wherein R₂ is —CH₃. In another embodiment is a compound of Formula (Ia),wherein R₂ is —CH₂CH₃. In another embodiment is a compound of Formula(Ia), wherein R₂ is C₁-C₆alkyl-OR₆. In another embodiment is a compoundof Formula (Ia), wherein R₂ is C₁-C₆alkyl-OH. In another embodiment is acompound of Formula (Ia), wherein R₂ is C₁-C₆alkylC₃-C₆cycloalkyl. Inanother embodiment is a compound of Formula (Ia), wherein R₂ is—CH₂—C₃-C₆cycloalkyl. In another embodiment is a compound of Formula(Ia), wherein R₂ is —CH₂— cyclopropyl. In another embodiment is acompound of Formula (Ia), wherein R₂ is —CH₂— cyclobutyl. In anotherembodiment is a compound of Formula (Ia), wherein R₂ is —CH₂—cyclopentyl. In another embodiment is a compound of Formula (Ia),wherein R₂ is —CH₂— cyclohexyl. In another embodiment is a compound ofFormula (Ia), wherein R₂ is C₁-C₆alkylC₂-C₇heterocycloalkyl. In anotherembodiment is a compound of Formula (Ia), wherein R₂ is—CH₂—C₂-C₇heterocycloalkyl. In another embodiment is a compound ofFormula (Ia), wherein R₂ is C₁-C₆alkyl-CO₂R₆. In another embodiment is acompound of Formula (Ia), wherein R₂ is C₁-C₆alkyl-CO₂CH₃. In anotherembodiment is a compound of Formula (Ia), wherein R₂ isC₁-C₆alkyl-CO₂CH₂CH₃. In another embodiment is a compound of Formula(Ia), wherein R₂ is optionally substituted C₁-C₆alkylaryl. In anotherembodiment is a compound of Formula (Ia), wherein R₂ is optionallysubstituted C₁-C₆alkylheteroaryl.

In another embodiment is a compound of Formula (Ia), wherein Z is asingle bond. In another embodiment is a compound of Formula (Ia),wherein Z is a double bond. In another embodiment is a compound ofFormula (Ia), wherein Z is —CH₂—. In another embodiment is a compound ofFormula (Ia), wherein Z is —O—.

In another embodiment is a compound of Formula (Ia), having thestructure of Formula (Ia′):

wherein:R₁ is aryl or heteroaryl, wherein aryl and heteroaryl are optionallysubstituted with one or more R₄;R₂ is H, C₁-C₆alkyl, C₁-C₆alkyl-OR₆, C₁-C₆alkylC₃-C₆cycloalkyl,C₁-C₆alkylC₂-C₇heterocycloalkyl, C₁-C₆alkyl-CO₂R₆, optionallysubstituted C₁-C₆alkylaryl, or optionally substitutedC₁-C₆alkylheteroaryl;each R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀,—N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₇heterocycloalkyl, aryl, andheteroaryl;R₆ is H, or C₁-C₆alkyl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, C₁-C₆alkylaryl, or C₁-C₆alkylheteroaryl; andR₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, C₁-C₆alkylaryl, or C₁-C₆alkylheteroaryl;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In one embodiment is a compound of Formula (Ia′), wherein R₁ is aryloptionally substituted with one or more R₄. In another embodiment is acompound of Formula (Ia′), wherein R₁ is phenyl optionally substitutedwith one or more R₄. In another embodiment is a compound of Formula(Ia′), wherein R₁ is phenyl substituted with one or more R₄, whereineach R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl.In another embodiment is a compound of Formula (Ia′), wherein R₁ isphenyl substituted with one or more R₄, wherein each R₄ is independentlyselected F, Cl, Br, I, —CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, andC₁-C₆alkyl. In another embodiment is a compound of Formula (Ia′),wherein R₁ is 4-chlorophenyl.

In another embodiment is a compound of Formula (Ia′) wherein R₁ isheteroaryl optionally substituted with one or more R₄. In anotherembodiment is a compound of Formula (Ia′), wherein R₁ is heteroarylsubstituted with one or more R₄, wherein each R₄ is independentlyselected from F, Cl, Br, I, —CN, —NO₂, —CF₃, —OR₉, —OCF₃, —NR₈R₉,—C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl. In another embodimentis a compound of Formula (Ia′), wherein R₁ is heteroaryl substitutedwith one or more R₄, wherein each R₄ is independently selected F, Cl,Br, I, —CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, and C₁-C₆alkyl. Inanother embodiment is a compound of Formula (Ia′), wherein heteroaryl ispyridyl.

In another embodiment is a compound of Formula (Ia′), wherein R₂ is H.In another embodiment is a compound of Formula (Ia′), wherein R₂ isC₁-C₆alkyl. In a further embodiment is a compound of Formula (Ia′),wherein R₂ is —CH₃. In another embodiment is a compound of Formula(Ia′), wherein R₂ is —CH₂CH₃. In another embodiment is a compound ofFormula (Ia′), wherein R₂ is C₁-C₆alkyl-OR₆. In another embodiment is acompound of Formula (Ia′), wherein R₂ is C₁-C₆alkyl-OH. In anotherembodiment is a compound of Formula (Ia′), wherein R₂ isC₁-C₆alkylC₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (Ia′), wherein R₂ is —CH₂—C₃-C₆cycloalkyl. In another embodimentis a compound of Formula (Ia′), wherein R₂ is —CH₂— cyclopropyl. Inanother embodiment is a compound of Formula (Ia′), wherein R₂ is —CH₂—cyclobutyl. In another embodiment is a compound of Formula (Ia′),wherein R₂ is —CH₂— cyclopentyl. In another embodiment is a compound ofFormula (Ia′), wherein R₂ is —CH₂— cyclohexyl. In another embodiment isa compound of Formula (Ia′), wherein R₂ isC₁-C₆alkylC₂-C₇heterocycloalkyl. In another embodiment is a compound ofFormula (Ia′), wherein R₂ is —CH₂—C₂-C₇heterocycloalkyl. In anotherembodiment is a compound of Formula (Ia′), wherein R₂ isC₁-C₆alkyl-CO₂R₆. In another embodiment is a compound of Formula (Ia′),wherein R₂ is C₁-C₆alkyl-CO₂CH₃. In another embodiment is a compound ofFormula (Ia′), wherein R₂ is C₁-C₆alkyl-CO₂CH₂CH₃. In another embodimentis a compound of Formula (Ia′), wherein R₂ is optionally substitutedC₁-C₆alkylaryl. In another embodiment is a compound of Formula (Ia′),wherein R₂ is optionally substituted C₁-C₆alkylheteroaryl.

In another embodiment is a compound of Formula (Ia), having thestructure of Formula (Ia″):

wherein:R₂ is H, C₁-C₆alkyl, C₁-C₆alkyl-OR₆, C₁-C₆alkylC₃-C₆cycloalkyl,C₁-C₆alkylC₂-C₇heterocycloalkyl, C₁-C₆alkyl-CO₂R₆, optionallysubstituted C₁-C₆alkylaryl, or optionally substitutedC₁-C₆alkylheteroaryl; andR₆ is H, or C₁-C₆alkyl;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.In one embodiment is a compound of Formula (Ia″), wherein R₂ is H. Inanother embodiment is a compound of Formula (Ia″), wherein R₂ isC₁-C₆alkyl. In a further embodiment is a compound of Formula (Ia″),wherein R₂ is —CH₃. In another embodiment is a compound of Formula(Ia″), wherein R₂ is —CH₂CH₃. In another embodiment is a compound ofFormula (Ia″), wherein R₂ is C₁-C₆alkyl-OR₆. In another embodiment is acompound of Formula (Ia″), wherein R₂ is C₁-C₆alkyl-OH. In anotherembodiment is a compound of Formula (Ia″), wherein R₂ isC₁-C₆alkylC₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (Ia″), wherein R₂ is —CH₂—C₃-C₆cycloalkyl. In another embodimentis a compound of Formula (Ia″), wherein R₂ is —CH₂— cyclopropyl. Inanother embodiment is a compound of Formula (Ia″), wherein R₂ is —CH₂—cyclobutyl. In another embodiment is a compound of Formula (Ia″),wherein R₂ is —CH₂— cyclopentyl. In another embodiment is a compound ofFormula (Ia″), wherein R₂ is —CH₂— cyclohexyl. In another embodiment isa compound of Formula (Ia″), wherein R₂ isC₁-C₆alkylC₂-C₇heterocycloalkyl. In another embodiment is a compound ofFormula (Ia″), wherein R₂ is —CH₂—C₂-C₇heterocycloalkyl. In anotherembodiment is a compound of Formula (Ia″), wherein R₂ isC₁-C₆alkyl-CO₂R₆. In another embodiment is a compound of Formula (Ia″),wherein R₂ is C₁-C₆alkyl-CO₂CH₃. In another embodiment is a compound ofFormula (Ia″), wherein R₂ is C₁-C₆alkyl-CO₂CH₂CH₃. In another embodimentis a compound of Formula (Ia″), wherein R₂ is optionally substitutedC₁-C₆alkylaryl. In another embodiment is a compound of Formula (Ia″),wherein R₂ is optionally substituted C₁-C₆alkylheteroaryl.

In another embodiment is a compound of Formula (Ib):

wherein:Z is a single bond, double bond, —CH₂—, or —O—;R₁ is aryl or heteroaryl, wherein aryl and heteroaryl are optionallysubstituted with one or more R₄;R₂ is H, C₁-C₆alkyl, C₁-C₆alkyl-OR₆, C₁-C₆alkylC₃-C₆cycloalkyl,C₁-C₆alkylC₂-C₇heterocycloalkyl, C₁-C₆alkyl-CO₂R₆, optionallysubstituted C₁-C₆alkylaryl, or optionally substitutedC₁-C₆alkylheteroaryl;R₃ and R₅ are each independently H, or C₁-C₆alkyl; orR₃ and R₅ together form an optionally substituted C₃-C₆cycloalkyl ring,optionally substituted C₂-C₇heterocycloalkyl ring, optionallysubstituted aryl ring, or an optionally substituted heteroaryl ring;each R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀,—N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₇heterocycloalkyl, aryl, andheteroaryl;R₆ is H, or C₁-C₆alkyl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, C₁-C₆alkylaryl, or C₁-C₆alkylheteroaryl;R₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, C₁-C₆alkylaryl, or C₁-C₆alkylheteroaryl;R₁₁ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylC₃-C₆cycloalkyl,C₁-C₆alkylaryl, or C₁-C₆alkylheteroaryl;R₁₂ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylC₃-C₆cycloalkyl,C₁-C₆alkylaryl, or C₁-C₆alkylheteroaryl; or R₁₁ and R₁₂ together withthe nitrogen to which they are attached form an optionally substitutedC₂-C₇heterocycloalkyl ring; andR₁₃ and R₁₄ are each independently H, or C₁-C₆alkyl;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In another embodiment is a compound of Formula (Ib) wherein R₁₁ and R₁₂are each C₁-C₆alkyl. In another embodiment is a compound of Formula (Ib)wherein R₁₁ and R₁₂ are each —CH₃. In another embodiment is a compoundof Formula (Ib) wherein R₁₁ is H and R₁₂ is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (Ib) wherein R₁₁ is H and R₁₂ is—CH₃. In another embodiment is a compound of Formula (Ib) wherein R₁₁ isH and R₁₂ is C₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (Ib) wherein R₁₁ is H and R₁₂ is C₁-C₆alkylC₃-C₆cycloalkyl. Inanother embodiment is a compound of Formula (Ib) wherein R₁₁ is H andR₁₂ is C₁-C₆alkylaryl. In another embodiment is a compound of Formula(Ib) wherein R₁₁ is H and R₁₂ is C₁-C₆alkylheteroaryl.

In another embodiment is a compound of Formula (Ib) wherein R₁₃ and R₁₄are each H. In another embodiment is a compound of Formula (Ib) whereinR₁₃ and R₁₄ are each —CH₃.

In another embodiment is a compound of Formula (Ib) wherein R₃ and R₅are each H. In another embodiment is a compound of Formula (Ib) whereinR₃ and R₅ are each —CH₃.

In another embodiment is a compound of Formula (Ib) wherein R₁₁ and R₁₂are each H.

In another embodiment is a compound of Formula (Ib), wherein R₂ is H. Inanother embodiment is a compound of Formula (Ib), wherein R₂ isC₁-C₆alkyl. In a further embodiment is a compound of Formula (Ib),wherein R₂ is —CH₃. In another embodiment is a compound of Formula (Ib),wherein R₂ is —CH₂CH₃. In another embodiment is a compound of Formula(Ib), wherein R₂ is C₁-C₆alkyl-OR₆. In another embodiment is a compoundof Formula (Ib), wherein R₂ is C₁-C₆alkyl-OH. In another embodiment is acompound of Formula (Ib), wherein R₂ is C₁-C₆alkylC₃-C₆cycloalkyl. Inanother embodiment is a compound of Formula (Ib), wherein R₂ is—CH₂—C₃-C₆cycloalkyl. In another embodiment is a compound of Formula(Ib), wherein R₂ is —CH₂— cyclopropyl. In another embodiment is acompound of Formula (Ib), wherein R₂ is —CH₂— cyclobutyl. In anotherembodiment is a compound of Formula (Ib), wherein R₂ is —CH₂—cyclopentyl. In another embodiment is a compound of Formula (Ib),wherein R₂ is —CH₂— cyclohexyl. In another embodiment is a compound ofFormula (Ib), wherein R₂ is C₁-C₆alkylC₂-C₇heterocycloalkyl. In anotherembodiment is a compound of Formula (Ib), wherein R₂ is—CH₂—C₂-C₇heterocycloalkyl. In another embodiment is a compound ofFormula (Ib), wherein R₂ is C₁-C₆alkyl-CO₂R₆. In another embodiment is acompound of Formula (Ib), wherein R₂ is C₁-C₆alkyl-CO₂CH₃. In anotherembodiment is a compound of Formula (Ib), wherein R₂ isC₁-C₆alkyl-CO₂CH₂CH₃. In another embodiment is a compound of Formula(Ib), wherein R₂ is optionally substituted C₁-C₆alkylaryl. In anotherembodiment is a compound of Formula (Ib), wherein R₂ is optionallysubstituted C₁-C₆alkylheteroaryl.

In another embodiment is a compound of Formula (Ib), wherein Z is asingle bond. In another embodiment is a compound of Formula (Ib),wherein Z is a double bond. In another embodiment is a compound ofFormula (Ib), wherein Z is —CH₂—. In another embodiment is a compound ofFormula (Ib), wherein Z is —O—.

In another embodiment is a compound of Formula (Ib), having thestructure of Formula (Ib′):

wherein:R₁ is aryl or heteroaryl, wherein aryl and heteroaryl are optionallysubstituted with one or more R₄;R₂ is H, C₁-C₆alkyl, C₁-C₆alkyl-OR₆, C₁-C₆alkylC₃-C₆cycloalkyl,C₁-C₆alkylC₂-C₇heterocycloalkyl, C₁-C₆alkyl-CO₂R₆, optionallysubstituted C₁-C₆alkylaryl, or optionally substitutedC₁-C₆alkylheteroaryl;each R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀,—N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₇heterocycloalkyl, aryl, andheteroaryl;R₆ is H, or C₁-C₆alkyl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, C₁-C₆alkylaryl, or C₁-C₆alkylheteroaryl; andR₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, C₁-C₆alkylaryl, or C₁-C₆alkylheteroaryl;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In one embodiment is a compound of Formula (Ib′), wherein R₁ is aryloptionally substituted with one or more R₄. In another embodiment is acompound of Formula (Ib′), wherein R₁ is phenyl optionally substitutedwith one or more R₄. In another embodiment is a compound of Formula(Ib′), wherein R₁ is phenyl substituted with one or more R₄, whereineach R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl.In another embodiment is a compound of Formula (Ib′), wherein R₁ isphenyl substituted with one or more R₄, wherein each R₄ is independentlyselected F, Cl, Br, I, —CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, andC₁-C₆alkyl. In another embodiment is a compound of Formula (Ib′),wherein R₁ is 4-chlorophenyl.

In another embodiment is a compound of Formula (Ib′) wherein R₁ isheteroaryl optionally substituted with one or more R₄. In anotherembodiment is a compound of Formula (Ib′), wherein R₁ is heteroarylsubstituted with one or more R₄, wherein each R₄ is independentlyselected from F, Cl, Br, I, —CN, —NO₂, —CF₃, —OR₉, —OCF₃, —NR₈R₉,—C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl. In another embodimentis a compound of Formula (Ib′), wherein R₁ is heteroaryl substitutedwith one or more R₄, wherein each R₄ is independently selected F, Cl,Br, I, —CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, and C₁-C₆alkyl. Inanother embodiment is a compound of Formula (Ib′), wherein heteroaryl ispyridyl.

In another embodiment is a compound of Formula (Ib′), wherein R₂ is H.In another embodiment is a compound of Formula (Ib′), wherein R₂ isC₁-C₆alkyl. In a further embodiment is a compound of Formula (Ib′),wherein R₂ is —CH₃. In another embodiment is a compound of Formula(Ib′), wherein R₂ is —CH₂CH₃. In another embodiment is a compound ofFormula (Ib′), wherein R₂ is C₁-C₆alkyl-OR₆. In another embodiment is acompound of Formula (Ib′), wherein R₂ is C₁-C₆alkyl-OH. In anotherembodiment is a compound of Formula (Ib′), wherein R₂ isC₁-C₆alkylC₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (Ib′), wherein R₂ is —CH₂—C₃-C₆cycloalkyl. In another embodimentis a compound of Formula (Ib′), wherein R₂ is —CH₂— cyclopropyl. Inanother embodiment is a compound of Formula (Ib′), wherein R₂ is —CH₂—cyclobutyl. In another embodiment is a compound of Formula (Ib′),wherein R₂ is —CH₂— cyclopentyl. In another embodiment is a compound ofFormula (Ib′), wherein R₂ is —CH₂— cyclohexyl. In another embodiment isa compound of Formula (Ib′), wherein R₂ isC₁-C₆alkylC₂-C₇heterocycloalkyl. In another embodiment is a compound ofFormula (Ib′), wherein R₂ is —CH₂—C₂-C₇heterocycloalkyl. In anotherembodiment is a compound of Formula (Ib′), wherein R₂ isC₁-C₆alkyl-CO₂R₆. In another embodiment is a compound of Formula (Ib′),wherein R₂ is C₁-C₆alkyl-CO₂CH₃. In another embodiment is a compound ofFormula (Ib′), wherein R₂ is C₁-C₆alkyl-CO₂CH₂CH₃. In another embodimentis a compound of Formula (Ib′), wherein R₂ is optionally substitutedC₁-C₆alkylaryl. In another embodiment is a compound of Formula (Ib′),wherein R₂ is optionally substituted C₁-C₆alkylheteroaryl.

In another embodiment is a compound of Formula (Ib), having thestructure of Formula (Ib″):

wherein:R₂ is H, C₁-C₆alkyl, C₁-C₆alkyl-OR₆, C₁-C₆alkylC₃-C₆cycloalkyl,C₁-C₆alkylC₂-C₇heterocycloalkyl, C₁-C₆alkyl-CO₂R₆, optionallysubstituted C₁-C₆alkylaryl, or optionally substitutedC₁-C₆alkylheteroaryl;R₆ is H, or C₁-C₆alkyl;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.In one embodiment is a compound of Formula (Ib″), wherein R₂ is H. Inanother embodiment is a compound of Formula (Ib″), wherein R₂ isC₁-C₆alkyl. In a further embodiment is a compound of Formula (Ib″),wherein R₂ is —CH₃. In another embodiment is a compound of Formula(Ib″), wherein R₂ is —CH₂CH₃. In another embodiment is a compound ofFormula (Ib″), wherein R₂ is C₁-C₆alkyl-OR₆. In another embodiment is acompound of Formula (Ib″), wherein R₂ is C₁-C₆alkyl-OH. In anotherembodiment is a compound of Formula (Ib″), wherein R₂ isC₁-C₆alkylC₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (Ib″), wherein R₂ is —CH₂—C₃-C₆cycloalkyl. In another embodimentis a compound of Formula (Ib″), wherein R₂ is —CH₂— cyclopropyl. Inanother embodiment is a compound of Formula (Ib″), wherein R₂ is —CH₂—cyclobutyl. In another embodiment is a compound of Formula (Ib″),wherein R₂ is —CH₂— cyclopentyl. In another embodiment is a compound ofFormula (Ib″), wherein R₂ is —CH₂— cyclohexyl. In another embodiment isa compound of Formula (Ib″), wherein R₂ isC₁-C₆alkylC₂-C₇heterocycloalkyl. In another embodiment is a compound ofFormula (Ib″), wherein R₂ is —CH₂—C₂-C₇heterocycloalkyl. In anotherembodiment is a compound of Formula (Ib″), wherein R₂ isC₁-C₆alkyl-CO₂R₆. In another embodiment is a compound of Formula (Ib″),wherein R₂ is C₁-C₆alkyl-CO₂CH₃. In another embodiment is a compound ofFormula (Ib″), wherein R₂ is C₁-C₆alkyl-CO₂CH₂CH₃. In another embodimentis a compound of Formula (Ib″), wherein R₂ is optionally substitutedC₁-C₆alkylaryl. In another embodiment is a compound of Formula (Ib″),wherein R₂ is optionally substituted C₁-C₆alkylheteroaryl.

In another embodiment is a compound of Formula (II):

wherein:X⁻ is a counterion;Z is a single bond, double bond, —CH₂—, or —O—;R₁ is aryl or heteroaryl, wherein aryl and heteroaryl are optionallysubstituted with one or more R₄;R_(2a) is C₁-C₆alkyl, —C₁-C₆alkyl-OR₅, or —C₁-C₆alkylC₃-C₆cycloalkyl;R₂ is C₁-C₆alkyl, —C₁-C₆alkyl-OR₆, —C₁-C₆alkylC₃-C₆cycloalkyl, or—C₁-C₆alkyl-CO₂R₆;R₃ and R₅ are each independently H, or C₁-C₆alkyl; orR₃ and R₅ together form an optionally substituted C₃-C₆cycloalkyl ring,optionally substituted C₂-C₇heterocycloalkyl ring, optionallysubstituted aryl ring, or an optionally substituted heteroaryl ring;each R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀,—N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₇heterocycloalkyl, aryl, andheteroaryl;R₆ is H, or C₁-C₆alkyl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, —C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl;R₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, —C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl;R₁₁ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, aryl, heteroaryl, —C₁-C₆alkylC₃-C₆cycloalkyl,—C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl;R₁₂ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, aryl, heteroaryl, —C₁-C₆alkylC₃-C₆cycloalkyl,—C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl; or R₁₁ and R₁₂ together withthe nitrogen to which they are attached form an optionally substitutedC₂-C₇heterocycloalkyl ring; andR₁₃ and R₁₄ are each independently H, or C₁-C₆alkyl;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In one embodiment is a compound of Formula (II), wherein R₁ is aryloptionally substituted with one or more R₄. In another embodiment is acompound of Formula (II), wherein R₁ is phenyl optionally substitutedwith one or more R₄. In another embodiment is a compound of Formula(II), wherein R₁ is phenyl substituted with one or more R₄, wherein eachR₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃, —OR₉,—OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl. Inanother embodiment is a compound of Formula (II), wherein R₁ is phenylsubstituted with one or more R₄, wherein each R₄ is independentlyselected F, Cl, Br, I, —CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, andC₁-C₆alkyl. In another embodiment is a compound of Formula (II), whereinR₁ is 4-chlorophenyl.

In another embodiment is a compound of Formula (II) wherein R₁ isheteroaryl optionally substituted with one or more R₄. In anotherembodiment is a compound of Formula (II), wherein R₁ is heteroarylsubstituted with one or more R₄, wherein each R₄ is independentlyselected from F, Cl, Br, I, —CN, —NO₂, —CF₃, —OR₉, —OCF₃, —NR₈R₉,—C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl. In another embodimentis a compound of Formula (II), wherein R₁ is heteroaryl substituted withone or more R₄, wherein each R₄ is independently selected F, Cl, Br, I,—CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, and C₁-C₆alkyl. In anotherembodiment is a compound of Formula (II), wherein heteroaryl is pyridyl.

In another embodiment is a compound of Formula (II) wherein R₁₁ and R₁₂are each C₁-C₆alkyl. In another embodiment is a compound of Formula (II)wherein R₁₁ and R₁₂ are each —CH₃. In another embodiment is a compoundof Formula (II) wherein R₁₁ is H and R₁₂ is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (II) wherein R₁₁ is H and R₁₂ is—CH₃. In another embodiment is a compound of Formula (II) wherein R₁₁ isH and R₁₂ is C₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (II) wherein R₁₁ is H and R₁₂ is C₁-C₆alkylC₃-C₆cycloalkyl. Inanother embodiment is a compound of Formula (II) wherein R₁₁ is H andR₁₂ is C₁-C₆alkylaryl. In another embodiment is a compound of Formula(II) wherein R₁₁ is H and R₁₂ is C₁-C₆alkylheteroaryl.

In another embodiment is a compound of Formula (II) wherein R₁₃ and R₁₄are each H. In another embodiment is a compound of Formula (II) whereinR₁₃ and R₁₄ are each —CH₃.

In another embodiment is a compound of Formula (II) wherein R₃ and R₅are each H. In another embodiment is a compound of Formula (II) whereinR₃ and R₅ are each —CH₃.

In another embodiment is a compound of Formula (II) wherein R₁₁ and R₁₂are each H.

In another embodiment is a compound of Formula (II), wherein R₂ isC₁-C₆alkyl. In a further embodiment is a compound of Formula (II),wherein R₂ is —CH₃. In another embodiment is a compound of Formula (II),wherein R₂ is —CH₂CH₃. In another embodiment is a compound of Formula(II), wherein R₂ is C₁-C₆alkyl-OR₆. In another embodiment is a compoundof Formula (II), wherein R₂ is C₁-C₆alkyl-OH. In another embodiment is acompound of Formula (II), wherein R₂ is C₁-C₆alkylC₃-C₆cycloalkyl. Inanother embodiment is a compound of Formula (II), wherein R₂ is—CH₂—C₃-C₆cycloalkyl. In another embodiment is a compound of Formula(II), wherein R₂ is —CH₂-cyclopropyl. In another embodiment is acompound of Formula (II), wherein R₂ is —CH₂— cyclobutyl. In anotherembodiment is a compound of Formula (II), wherein R₂ is—CH₂-cyclopentyl. In another embodiment is a compound of Formula (II),wherein R₂ is —CH₂-cyclohexyl. In another embodiment is a compound ofFormula (II), wherein R₂ is C₁-C₆alkyl-CO₂R₆. In another embodiment is acompound of Formula (II), wherein R₂ is C₁-C₆alkyl-CO₂CH₃. In anotherembodiment is a compound of Formula (II), wherein R₂ isC₁-C₆alkyl-CO₂CH₂CH₃.

In another embodiment is a compound of Formula (II), wherein R_(2a) isC₁-C₆alkyl. In a further embodiment is a compound of Formula (II),wherein R_(2a) is —CH₃. In another embodiment is a compound of Formula(II), wherein R_(2a) is —CH₂CH₃. In another embodiment is a compound ofFormula (II), wherein R_(2a) is C₁-C₆alkyl-OR₅. In another embodiment isa compound of Formula (II), wherein R_(2a) is C₁-C₆alkyl-OH. In anotherembodiment is a compound of Formula (II), wherein R_(2a) isC₁-C₆alkylC₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (II), wherein R_(2a) is —CH₂—C₃-C₆cycloalkyl. In anotherembodiment is a compound of Formula (II), wherein R_(2a) is—CH₂-cyclopropyl. In another embodiment is a compound of Formula (II),wherein R_(2a) is —CH₂-cyclobutyl. In another embodiment is a compoundof Formula (II), wherein R_(2a) is —CH₂-cyclopentyl. In anotherembodiment is a compound of Formula (II), wherein R_(2a) is—CH₂-cyclohexyl.

In another embodiment is a compound of Formula (II), wherein R₂ isC₁-C₆alkyl and R_(2a) is C₁-C₆alkyl. In another embodiment is a compoundof Formula (II), wherein R₂ is —CH₃ and R_(2a) is —CH₃. In anotherembodiment is a compound of Formula (II), wherein R₂ is —CH₂CH₃ andR_(2a) is —CH₃. In another embodiment is a compound of Formula (II),wherein R₂ is —C₁-C₆alkyl-OR₆ and R_(2a) is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (II), wherein R₂ is —C₁-C₆alkyl-OHand R_(2a) is C₁-C₆alkyl. In another embodiment is a compound of Formula(II), wherein R₂ is —C₁-C₆alkyl-OH and R_(2a) is —CH₃. In anotherembodiment is a compound of Formula (II), wherein R₂ is—C₁-C₆alkylC₃-C₆cycloalkyl and R_(2a) is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (II), wherein R₂ is—C₁-C₆alkylC₃-C₆cycloalkyl and R_(2a) is —CH₃. In another embodiment isa compound of Formula (II), wherein R₂ is —CH₂—C₃-C₆cycloalkyl andR_(2a) is —CH₃. In another embodiment is a compound of Formula (II),wherein R₂ is —C₁-C₆alkyl-CO₂R₆ and R_(2a) is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (II), wherein R₂ is—C₁-C₆alkyl-CO₂CH₃ and R_(2a) is —CH₃.

In another embodiment is a compound of Formula (II), wherein Z is asingle bond. In another embodiment is a compound of Formula (II),wherein Z is a double bond. In another embodiment is a compound ofFormula (II), wherein Z is —CH₂—. In another embodiment is a compound ofFormula (II), wherein Z is —O—.

In another embodiment is a compound of Formula (II), wherein X⁻ is Cl⁻.In another embodiment is a compound of Formula (II), wherein X⁻ is Br⁻.In another embodiment is a compound of Formula (II), wherein X⁻ is I⁻.In another embodiment is a compound of Formula (II), wherein X⁻ isCF₃CO₂ ⁻. In another embodiment is a compound of Formula (II), whereinX⁻ is Cl⁻, Br⁻, I⁻, or CF₃CO₂ ⁻.

In another embodiment is a compound of Formula (II), having thestructure of Formula (II′):

wherein:X⁻ is a counterion;R₁ is aryl or heteroaryl, wherein aryl and heteroaryl are optionallysubstituted with one or more R₄;R_(2a) is C₁-C₆alkyl, —C₁-C₆alkyl-OR₅, or —C₁-C₆alkylC₃-C₆cycloalkyl;R₂ is C₁-C₆alkyl, —C₁-C₆alkyl-OR₆, —C₁-C₆alkylC₃-C₆cycloalkyl, or—C₁-C₆alkyl-CO₂R₆;each R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀,—N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₇heterocycloalkyl, aryl, andheteroaryl;R₅ is H, or C₁-C₆alkyl;R₆ is H, or C₁-C₆alkyl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, —C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl; andR₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, —C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In one embodiment is a compound of Formula (II′), wherein R₁ is aryloptionally substituted with one or more R₄. In another embodiment is acompound of Formula (II′), wherein R₁ is phenyl optionally substitutedwith one or more R₄. In another embodiment is a compound of Formula(II′), wherein R₁ is phenyl substituted with one or more R₄, whereineach R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl.In another embodiment is a compound of Formula (II′), wherein R₁ isphenyl substituted with one or more R₄, wherein each R₄ is independentlyselected F, Cl, Br, I, —CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, andC₁-C₆alkyl. In another embodiment is a compound of Formula (II′),wherein R₁ is 4-chlorophenyl.

In another embodiment is a compound of Formula (II′) wherein R₁ isheteroaryl optionally substituted with one or more R₄. In anotherembodiment is a compound of Formula (II′), wherein R₁ is heteroarylsubstituted with one or more R₄, wherein each R₄ is independentlyselected from F, Cl, Br, I, —CN, —NO₂, —CF₃, —OR₉, —OCF₃, —NR₈R₉,—C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl. In another embodimentis a compound of Formula (II′), wherein R₁ is heteroaryl substitutedwith one or more R₄, wherein each R₄ is independently selected F, Cl,Br, I, —CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, and C₁-C₆alkyl. Inanother embodiment is a compound of Formula (II′), wherein heteroaryl ispyridyl.

In another embodiment is a compound of Formula (II′), wherein R₂ isC₁-C₆alkyl. In a further embodiment is a compound of Formula (II′),wherein R₂ is —CH₃. In another embodiment is a compound of Formula(II′), wherein R₂ is —CH₂CH₃. In another embodiment is a compound ofFormula (II′), wherein R₂ is C₁-C₆alkyl-OR₆. In another embodiment is acompound of Formula (II′), wherein R₂ is C₁-C₆alkyl-OH. In anotherembodiment is a compound of Formula (II′), wherein R₂ isC₁-C₆alkylC₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (II′), wherein R₂ is —CH₂—C₃-C₆cycloalkyl. In another embodimentis a compound of Formula (II′), wherein R₂ is —CH₂-cyclopropyl. Inanother embodiment is a compound of Formula (II′), wherein R₂ is—CH₂-cyclobutyl. In another embodiment is a compound of Formula (II′),wherein R₂ is —CH₂— cyclopentyl. In another embodiment is a compound ofFormula (II′), wherein R₂ is —CH₂— cyclohexyl. In another embodiment isa compound of Formula (II′), wherein R₂ is C₁-C₆alkyl-CO₂R₆. In anotherembodiment is a compound of Formula (II′), wherein R₂ isC₁-C₆alkyl-CO₂CH₃. In another embodiment is a compound of Formula (II′),wherein R₂ is C₁-C₆alkyl-CO₂CH₂CH₃.

In another embodiment is a compound of Formula (II′), wherein R_(2a) isC₁-C₆alkyl. In a further embodiment is a compound of Formula (II′),wherein R_(2a) is —CH₃. In another embodiment is a compound of Formula(II′), wherein R_(2a) is —CH₂CH₃. In another embodiment is a compound ofFormula (II′), wherein R_(2a) is C₁-C₆alkyl-OR₅. In another embodimentis a compound of Formula (II′), wherein R_(2a) is C₁-C₆alkyl-OH. Inanother embodiment is a compound of Formula (II′), wherein R_(2a) isC₁-C₆alkylC₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (II′), wherein R_(2a) is —CH₂—C₃-C₆cycloalkyl. In anotherembodiment is a compound of Formula (II′), wherein R_(2a) is—CH₂-cyclopropyl. In another embodiment is a compound of Formula (II′),wherein R_(2a) is —CH₂-cyclobutyl. In another embodiment is a compoundof Formula (II′), wherein R_(2a) is —CH₂-cyclopentyl. In anotherembodiment is a compound of Formula (II′), wherein R_(2a) is—CH₂-cyclohexyl.

In another embodiment is a compound of Formula (II′), wherein R₂ isC₁-C₆alkyl and R_(2a) is C₁-C₆alkyl. In another embodiment is a compoundof Formula (II′), wherein R₂ is —CH₃ and R_(2a) is —CH₃. In anotherembodiment is a compound of Formula (II′), wherein R₂ is —CH₂CH₃ andR_(2a) is —CH₃. In another embodiment is a compound of Formula (II′),wherein R₂ is —C₁-C₆alkyl-OR₆ and R_(2a) is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (II′), wherein R₂ is —C₁-C₆alkyl-OHand R_(2a) is C₁-C₆alkyl. In another embodiment is a compound of Formula(II′), wherein R₂ is —C₁-C₆alkyl-OH and R_(2a) is —CH₃. In anotherembodiment is a compound of Formula (II′), wherein R₂ is—C₁-C₆alkylC₃-C₆cycloalkyl and R_(2a) is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (II′), wherein R₂ is—C₁-C₆alkylC₃-C₆cycloalkyl and R_(2a) is —CH₃. In another embodiment isa compound of Formula (II′), wherein R₂ is —CH₂—C₃-C₆cycloalkyl andR_(2a) is —CH₃. In another embodiment is a compound of Formula (II′),wherein R₂ is —C₁-C₆alkyl-CO₂R₆ and R_(2a) is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (II′), wherein R₂ is—C₁-C₆alkyl-CO₂CH₃ and R_(2a) is —CH₃.

In another embodiment is a compound of Formula (II′), wherein X⁻ is Cl⁻.In another embodiment is a compound of Formula (II′), wherein X⁻ is Br⁻.In another embodiment is a compound of Formula (II′), wherein X⁻ is I⁻.In another embodiment is a compound of Formula (II′), wherein X⁻ isCF₃CO₂. In another embodiment is a compound of Formula (II′), wherein X⁻is Cl⁻, Br⁻, I⁻, or CF₃CO₂ ⁻.

In another embodiment is a compound of Formula (II), having thestructure of Formula (II″):

wherein:X⁻ is a counterion;R_(2a) is C₁-C₆alkyl;R₂ is C₁-C₆alkyl, —C₁-C₆alkyl-OR₆, —C₁-C₆alkylC₃-C₆cycloalkyl, or—C₁-C₆alkyl-CO₂R₆; andR₆ is H, or C₁-C₆alkyl;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In one embodiment is a compound of Formula (II″), wherein R₂ isC₁-C₆alkyl. In a further embodiment is a compound of Formula (II″),wherein R₂ is —CH₃. In another embodiment is a compound of Formula(II″), wherein R₂ is —CH₂CH₃. In another embodiment is a compound ofFormula (II″), wherein R₂ is C₁-C₆alkyl-OR₆. In another embodiment is acompound of Formula (II″), wherein R₂ is C₁-C₆alkyl-OH. In anotherembodiment is a compound of Formula (II″), wherein R₂ isC₁-C₆alkylC₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (II″), wherein R₂ is —CH₂—C₃-C₆cycloalkyl. In another embodimentis a compound of Formula (II″), wherein R₂ is —CH₂-cyclopropyl. Inanother embodiment is a compound of Formula (II″), wherein R₂ is—CH₂-cyclobutyl. In another embodiment is a compound of Formula (II″),wherein R₂ is —CH₂-cyclopentyl. In another embodiment is a compound ofFormula (II″), wherein R₂ is —CH₂— cyclohexyl. In another embodiment isa compound of Formula (II″), wherein R₂ is C₁-C₆alkyl-CO₂R₆. In anotherembodiment is a compound of Formula (II″), wherein R₂ isC₁-C₆alkyl-CO₂CH₃. In another embodiment is a compound of Formula (II″),wherein R₂ is C₁-C₆alkyl-CO₂CH₂CH₃.

In another embodiment is a compound of Formula (II″), wherein R_(2a) isC₁-C₆alkyl. In a further embodiment is a compound of Formula (II″),wherein R_(2a) is —CH₃. In another embodiment is a compound of Formula(II″), wherein R_(2a) is —CH₂CH₃.

In another embodiment is a compound of Formula (II″), wherein R₂ isC₁-C₆alkyl and R_(2a) is C₁-C₆alkyl. In another embodiment is a compoundof Formula (II″), wherein R₂ is —CH₃ and R_(2a) is —CH₃. In anotherembodiment is a compound of Formula (II″), wherein R₂ is —CH₂CH₃ andR_(2a) is —CH₃. In another embodiment is a compound of Formula (II″),wherein R₂ is —C₁-C₆alkyl-OR₆ and R_(2a) is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (II″), wherein R₂ is —C₁-C₆alkyl-OHand R_(2a) is C₁-C₆alkyl. In another embodiment is a compound of Formula(II″), wherein R₂ is —C₁-C₆alkyl-OH and R_(2a) is —CH₃. In anotherembodiment is a compound of Formula (II″), wherein R₂ is—C₁-C₆alkylC₃-C₆cycloalkyl and R_(2a) is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (II″), wherein R₂ is—C₁-C₆alkylC₃-C₆cycloalkyl and R_(2a) is —CH₃. In another embodiment isa compound of Formula (II″), wherein R₂ is —CH₂—C₃-C₆cycloalkyl andR_(2a) is —CH₃. In another embodiment is a compound of Formula (II″),wherein R₂ is —C₁-C₆alkyl-CO₂R₆ and R_(2a) is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (II″), wherein R₂ is—C₁-C₆alkyl-CO₂CH₃ and R_(2a) is —CH₃.

In another embodiment is a compound of Formula (II″), wherein X⁻ is Cl⁻.In another embodiment is a compound of Formula (II″), wherein X⁻ is Br⁻.In another embodiment is a compound of Formula (II″), wherein X⁻ is I⁻.In another embodiment is a compound of Formula (II″), wherein X⁻ isCF₃CO₂. In another embodiment is a compound of Formula (II″), wherein Xis Cl⁻, Br⁻, I⁻, or CF₃CO₂ ⁻.

In another embodiment is a compound of Formula (IIa):

wherein:X⁻ is a counterion;Z is a single bond, double bond, —CH₂—, or —O—;R₁ is aryl or heteroaryl, wherein aryl and heteroaryl are optionallysubstituted with one or more R₄;R_(2a) is C₁-C₆alkyl, —C₁-C₆alkyl-OR₅, or —C₁-C₆alkylC₃-C₆cycloalkyl;R₂ is C₁-C₆alkyl, —C₁-C₆alkyl-OR₆, —C₁-C₆alkylC₃-C₆cycloalkyl, or—C₁-C₆alkyl-CO₂R₆;R₃ and R₅ are each independently H, or C₁-C₆alkyl; orR₃ and R₅ together form an optionally substituted C₃-C₆cycloalkyl ring,optionally substituted C₂-C₇heterocycloalkyl ring, optionallysubstituted aryl ring, or an optionally substituted heteroaryl ring;each R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀,—N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₇heterocycloalkyl, aryl, andheteroaryl;R₆ is H, or C₁-C₆alkyl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, —C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl;R₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, —C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl;R₁₁ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, aryl, heteroaryl, —C₁-C₆alkylC₃-C₆cycloalkyl,—C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl;R₁₂ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, aryl, heteroaryl, —C₁-C₆alkylC₃-C₆cycloalkyl,—C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl; or R₁₁ and R₁₂ together withthe nitrogen to which they are attached form an optionally substitutedC₂-C₇heterocycloalkyl ring; andR₁₃ and R₁₄ are each independently H, or C₁-C₆alkyl;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In one embodiment is a compound of Formula (IIa), wherein R₁ is aryloptionally substituted with one or more R₄. In another embodiment is acompound of Formula (IIa), wherein R₁ is phenyl optionally substitutedwith one or more R₄. In another embodiment is a compound of Formula(IIa), wherein R₁ is phenyl substituted with one or more R₄, whereineach R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl.In another embodiment is a compound of Formula (IIa), wherein R₁ isphenyl substituted with one or more R₄, wherein each R₄ is independentlyselected F, Cl, Br, I, —CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, andC₁-C₆alkyl. In another embodiment is a compound of Formula (IIa),wherein R₁ is 4-chlorophenyl.

In another embodiment is a compound of Formula (IIa) wherein R₁ isheteroaryl optionally substituted with one or more R₄. In anotherembodiment is a compound of Formula (IIa), wherein R₁ is heteroarylsubstituted with one or more R₄, wherein each R₄ is independentlyselected from F, Cl, Br, I, —CN, —NO₂, —CF₃, —OR₉, —OCF₃, —NR₈R₉,—C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl. In another embodimentis a compound of Formula (IIa), wherein R₁ is heteroaryl substitutedwith one or more R₄, wherein each R₄ is independently selected F, Cl,Br, I, —CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, and C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIa), wherein heteroaryl ispyridyl.

In another embodiment is a compound of Formula (IIa) wherein R₁₁ and R₁₂are each C₁-C₆alkyl. In another embodiment is a compound of Formula(IIa) wherein R₁₁ and R₁₂ are each —CH₃. In another embodiment is acompound of Formula (IIa) wherein R₁₁ is H and R₁₂ is C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIa) wherein R₁₁ is H andR₁₂ is —CH₃. In another embodiment is a compound of Formula (IIa)wherein R₁₁ is H and R₁₂ is C₃-C₆cycloalkyl. In another embodiment is acompound of Formula (IIa) wherein R₁₁ is H and R₁₂ isC₁-C₆alkylC₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (IIa) wherein R₁₁ is H and R₁₂ is C₁-C₆alkylaryl. In anotherembodiment is a compound of Formula (IIa) wherein R₁₁ is H and R₁₂ isC₁-C₆alkylheteroaryl.

In another embodiment is a compound of Formula (IIa) wherein R₁₃ and R₁₄are each H. In another embodiment is a compound of Formula (IIa) whereinR₁₃ and R₁₄ are each —CH₃.

In another embodiment is a compound of Formula (IIa) wherein R₃ and R₅are each H. In another embodiment is a compound of Formula (IIa) whereinR₃ and R₅ are each —CH₃.

In another embodiment is a compound of Formula (IIa) wherein R₁₁ and R₁₂are each H.

In another embodiment is a compound of Formula (IIa), wherein R₂ isC₁-C₆alkyl. In a further embodiment is a compound of Formula (IIa),wherein R₂ is —CH₃. In another embodiment is a compound of Formula (II),wherein R₂ is —CH₂CH₃. In another embodiment is a compound of Formula(IIa), wherein R₂ is C₁-C₆alkyl-OR₆. In another embodiment is a compoundof Formula (IIa), wherein R₂ is C₁-C₆alkyl-OH. In another embodiment isa compound of Formula (IIa), wherein R₂ is C₁-C₆alkylC₃-C₆cycloalkyl. Inanother embodiment is a compound of Formula (IIa), wherein R₂ is—CH₂—C₃-C₆cycloalkyl. In another embodiment is a compound of Formula(IIa), wherein R₂ is —CH₂-cyclopropyl. In another embodiment is acompound of Formula (IIa), wherein R₂ is —CH₂-cyclobutyl. In anotherembodiment is a compound of Formula (IIa), wherein R₂ is—CH₂-cyclopentyl. In another embodiment is a compound of Formula (IIa),wherein R₂ is —CH₂— cyclohexyl. In another embodiment is a compound ofFormula (IIa), wherein R₂ is C₁-C₆alkyl-CO₂R₆. In another embodiment isa compound of Formula (IIa), wherein R₂ is C₁-C₆alkyl-CO₂CH₃. In anotherembodiment is a compound of Formula (IIa), wherein R₂ isC₁-C₆alkyl-CO₂CH₂CH₃.

In another embodiment is a compound of Formula (IIa), wherein R_(2a) isC₁-C₆alkyl. In a further embodiment is a compound of Formula (IIa),wherein R_(2a) is —CH₃. In another embodiment is a compound of Formula(IIa), wherein R_(2a) is —CH₂CH₃. In another embodiment is a compound ofFormula (IIa), wherein R_(2a) is C₁-C₆alkyl-OR₅. In another embodimentis a compound of Formula (IIa), wherein R_(2a) is C₁-C₆alkyl-OH. Inanother embodiment is a compound of Formula (IIa), wherein R_(2a) isC₁-C₆alkylC₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (IIa), wherein R_(2a) is —CH₂—C₃-C₆cycloalkyl. In anotherembodiment is a compound of Formula (IIa), wherein R_(2a) is—CH₂-cyclopropyl. In another embodiment is a compound of Formula (IIa),wherein R_(2a) is —CH₂-cyclobutyl. In another embodiment is a compoundof Formula (IIa), wherein R_(2a) is —CH₂-cyclopentyl. In anotherembodiment is a compound of Formula (IIa), wherein R_(2a) is—CH₂-cyclohexyl.

In another embodiment is a compound of Formula (IIa), wherein R₂ isC₁-C₆alkyl and R_(2a) is C₁-C₆alkyl. In another embodiment is a compoundof Formula (IIa), wherein R₂ is —CH₃ and R_(2a) is —CH₃. In anotherembodiment is a compound of Formula (IIa), wherein R₂ is —CH₂CH₃ andR_(2a) is —CH₃. In another embodiment is a compound of Formula (IIa),wherein R₂ is —C₁-C₆alkyl-OR₆ and R_(2a) is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IIa), wherein R₂ is —C₁-C₆alkyl-OHand R_(2a) is C₁-C₆alkyl. In another embodiment is a compound of Formula(IIa), wherein R₂ is —C₁-C₆alkyl-OH and R_(2a) is —CH₃. In anotherembodiment is a compound of Formula (IIa), wherein R₂ is—C₁-C₆alkylC₃-C₆cycloalkyl and R_(2a) is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IIa), wherein R₂ is—C₁-C₆alkylC₃-C₆cycloalkyl and R_(2a) is —CH₃. In another embodiment isa compound of Formula (IIa), wherein R₂ is —CH₂—C₃-C₆cycloalkyl andR_(2a) is —CH₃. In another embodiment is a compound of Formula (IIa),wherein R₂ is —C₁-C₆alkyl-CO₂R₆ and R_(2a) is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IIa), wherein R₂ is—C₁-C₆alkyl-CO₂CH₃ and R_(2a) is —CH₃.

In another embodiment is a compound of Formula (IIa), wherein Z is asingle bond. In another embodiment is a compound of Formula (IIa),wherein Z is a double bond. In another embodiment is a compound ofFormula (IIa), wherein Z is —CH₂—. In another embodiment is a compoundof Formula (IIa), wherein Z is —O—.

In another embodiment is a compound of Formula (IIa), wherein X⁻ is Cl⁻.In another embodiment is a compound of Formula (IIa), wherein X⁻ is Br⁻.In another embodiment is a compound of Formula (IIa), wherein X⁻ is I⁻.In another embodiment is a compound of Formula (IIa), wherein X⁻ isCF₃CO₂ ⁻. In another embodiment is a compound of Formula (IIa), whereinX⁻ is Cl⁻, Br⁻, I⁻, or CF₃CO₂ ⁻.

In another embodiment is a compound of Formula (IIa), having thestructure of Formula (IIa′):

wherein:X⁻ is a counterion;R₁ is aryl or heteroaryl, wherein aryl and heteroaryl are optionallysubstituted with one or more R₄;R_(2a) is C₁-C₆alkyl, —C₁-C₆alkyl-OR₅, or —C₁-C₆alkylC₃-C₆cycloalkyl;R₂ is C₁-C₆alkyl, —C₁-C₆alkyl-OR₆, —C₁-C₆alkylC₃-C₆cycloalkyl, or—C₁-C₆alkyl-CO₂R₆;each R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀,—N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₇heterocycloalkyl, aryl, andheteroaryl;R₅ is H, or C₁-C₆alkyl;R₆ is H, or C₁-C₆alkyl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, —C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl; andR₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, —C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In one embodiment is a compound of Formula (IIa′), wherein R₁ is aryloptionally substituted with one or more R₄. In another embodiment is acompound of Formula (IIa′), wherein R₁ is phenyl optionally substitutedwith one or more R₄. In another embodiment is a compound of Formula(IIa′), wherein R₁ is phenyl substituted with one or more R₄, whereineach R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl.In another embodiment is a compound of Formula (IIa′), wherein R₁ isphenyl substituted with one or more R₄, wherein each R₄ is independentlyselected F, Cl, Br, I, —CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, andC₁-C₆alkyl. In another embodiment is a compound of Formula (IIa′),wherein R₁ is 4-chlorophenyl.

In another embodiment is a compound of Formula (IIa′) wherein R₁ isheteroaryl optionally substituted with one or more R₄. In anotherembodiment is a compound of Formula (IIa′), wherein R₁ is heteroarylsubstituted with one or more R₄, wherein each R₄ is independentlyselected from F, Cl, Br, I, —CN, —NO₂, —CF₃, —OR₉, —OCF₃, —NR₈R₉,—C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl. In another embodimentis a compound of Formula (IIa′), wherein R₁ is heteroaryl substitutedwith one or more R₄, wherein each R₄ is independently selected F, Cl,Br, I, —CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, and C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIa′), wherein heteroarylis pyridyl.

In another embodiment is a compound of Formula (IIa′), wherein R₂ isC₁-C₆alkyl. In a further embodiment is a compound of Formula (IIa′),wherein R₂ is —CH₃. In another embodiment is a compound of Formula(IIa′), wherein R₂ is —CH₂CH₃. In another embodiment is a compound ofFormula (IIa′), wherein R₂ is C₁-C₆alkyl-OR₆. In another embodiment is acompound of Formula (IIa′), wherein R₂ is C₁-C₆alkyl-OH. In anotherembodiment is a compound of Formula (IIa′), wherein R₂ isC₁-C₆alkylC₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (IIa′), wherein R₂ is —CH₂—C₃-C₆cycloalkyl. In anotherembodiment is a compound of Formula (IIa′), wherein R₂ is—CH₂-cyclopropyl. In another embodiment is a compound of Formula (IIa′),wherein R₂ is —CH₂-cyclobutyl. In another embodiment is a compound ofFormula (IIa′), wherein R₂ is —CH₂-cyclopentyl. In another embodiment isa compound of Formula (IIa′), wherein R₂ is —CH₂— cyclohexyl. In anotherembodiment is a compound of Formula (IIa′), wherein R₂ isC₁-C₆alkyl-CO₂R₆. In another embodiment is a compound of Formula (IIa′),wherein R₂ is C₁-C₆alkyl-CO₂CH₃. In another embodiment is a compound ofFormula (IIa′), wherein R₂ is C₁-C₆alkyl-CO₂CH₂CH₃.

In another embodiment is a compound of Formula (IIa′), wherein R_(2a) isC₁-C₆alkyl. In a further embodiment is a compound of Formula (IIa′),wherein R_(2a) is —CH₃. In another embodiment is a compound of Formula(IIa′), wherein R_(2a) is —CH₂CH₃. In another embodiment is a compoundof Formula (IIa′), wherein R_(2a) is C₁-C₆alkyl-OR₅. In anotherembodiment is a compound of Formula (IIa′), wherein R_(2a) isC₁-C₆alkyl-OH. In another embodiment is a compound of Formula (IIa′),wherein R_(2a) is C₁-C₆alkylC₃-C₆cycloalkyl. In another embodiment is acompound of Formula (IIa′), wherein R_(2a) is —CH₂—C₃-C₆cycloalkyl. Inanother embodiment is a compound of Formula (IIa′), wherein R_(2a) is—CH₂-cyclopropyl. In another embodiment is a compound of Formula (IIa′),wherein R_(2a) is —CH₂-cyclobutyl. In another embodiment is a compoundof Formula (IIa′), wherein R_(2a) is —CH₂-cyclopentyl. In anotherembodiment is a compound of Formula (IIa′), wherein R_(2a) is—CH₂-cyclohexyl.

In another embodiment is a compound of Formula (IIa′), wherein R₂ isC₁-C₆alkyl and R_(2a) is C₁-C₆alkyl. In another embodiment is a compoundof Formula (IIa′), wherein R₂ is —CH₃ and R_(2a) is —CH₃. In anotherembodiment is a compound of Formula (IIa′), wherein R₂ is —CH₂CH₃ andR_(2a) is —CH₃. In another embodiment is a compound of Formula (IIa′),wherein R₂ is —C₁-C₆alkyl-OR₆ and R_(2a) is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IIa′), wherein R₂ is —C₁-C₆alkyl-OHand R_(2a) is C₁-C₆alkyl. In another embodiment is a compound of Formula(IIa′), wherein R₂ is —C₁-C₆alkyl-OH and R_(2a) is —CH₃. In anotherembodiment is a compound of Formula (IIa′), wherein R₂ is—C₁-C₆alkylC₃-C₆cycloalkyl and R_(2a) is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IIa′), wherein R₂ is—C₁-C₆alkylC₃-C₆cycloalkyl and R_(2a) is —CH₃. In another embodiment isa compound of Formula (IIa′), wherein R₂ is —CH₂—C₃-C₆cycloalkyl andR_(2a) is —CH₃. In another embodiment is a compound of Formula (IIa′),wherein R₂ is —C₁-C₆alkyl-CO₂R₆ and R_(2a) is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IIa′), wherein R₂ is—C₁-C₆alkyl-CO₂CH₃ and R_(2a) is —CH₃.

In another embodiment is a compound of Formula (IIa′), wherein X⁻ isCl⁻. In another embodiment is a compound of Formula (IIa′), wherein X⁻is Br⁻. In another embodiment is a compound of Formula (IIa′), whereinX⁻ is I⁻. In another embodiment is a compound of Formula (IIa′), whereinX⁻ is CF₃CO₂. In another embodiment is a compound of Formula (IIa′),wherein X is Cl⁻, Br⁻, I⁻, or CF₃CO₂ ⁻.

In another embodiment is a compound of Formula (IIa), having thestructure of Formula (IIa″):

wherein:X⁻ is a counterion;R_(2a) is C₁-C₆alkyl;R₂ is C₁-C₆alkyl, —C₁-C₆alkyl-OR₆, —C₁-C₆alkylC₃-C₆cycloalkyl, or—C₁-C₆alkyl-CO₂R₆; andR₆ is H, or C₁-C₆alkyl;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In one embodiment is a compound of Formula (IIa″), wherein R₂ isC₁-C₆alkyl. In a further embodiment is a compound of Formula (IIa″),wherein R₂ is —CH₃. In another embodiment is a compound of Formula(IIa″), wherein R₂ is —CH₂CH₃. In another embodiment is a compound ofFormula (IIa″), wherein R₂ is C₁-C₆alkyl-OR₆. In another embodiment is acompound of Formula (IIa″), wherein R₂ is C₁-C₆alkyl-OH. In anotherembodiment is a compound of Formula (IIa″), wherein R₂ isC₁-C₆alkylC₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (IIa″), wherein R₂ is —CH₂—C₃-C₆cycloalkyl. In anotherembodiment is a compound of Formula (IIa″), wherein R₂ is—CH₂-cyclopropyl. In another embodiment is a compound of Formula (IIa″),wherein R₂ is —CH₂-cyclobutyl. In another embodiment is a compound ofFormula (IIa″), wherein R₂ is —CH₂-cyclopentyl. In another embodiment isa compound of Formula (IIa″), wherein R₂ is —CH₂— cyclohexyl. In anotherembodiment is a compound of Formula (IIa″), wherein R₂ isC₁-C₆alkyl-CO₂R₆. In another embodiment is a compound of Formula (IIa″),wherein R₂ is C₁-C₆alkyl-CO₂CH₃. In another embodiment is a compound ofFormula (IIa″), wherein R₂ is C₁-C₆alkyl-CO₂CH₂CH₃.

In another embodiment is a compound of Formula (IIa″), wherein R_(2a) isC₁-C₆alkyl. In a further embodiment is a compound of Formula (IIa″),wherein R_(2a) is —CH₃. In another embodiment is a compound of Formula(IIa″), wherein R_(2a) is —CH₂CH₃.

In another embodiment is a compound of Formula (IIa″), wherein R₂ isC₁-C₆alkyl and R_(2a) is C₁-C₆alkyl. In another embodiment is a compoundof Formula (IIa″), wherein R₂ is —CH₃ and R_(2a) is —CH₃. In anotherembodiment is a compound of Formula (IIa″), wherein R₂ is —CH₂CH₃ andR_(2a) is —CH₃. In another embodiment is a compound of Formula (IIa″),wherein R₂ is —C₁-C₆alkyl-OR₆ and R_(2a) is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IIa″), wherein R₂ is —C₁-C₆alkyl-OHand R_(2a) is C₁-C₆alkyl. In another embodiment is a compound of Formula(IIa″), wherein R₂ is —C₁-C₆alkyl-OH and R_(2a) is —CH₃. In anotherembodiment is a compound of Formula (IIa″), wherein R₂ is—C₁-C₆alkylC₃-C₆cycloalkyl and R_(2a) is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IIa″), wherein R₂ is—C₁-C₆alkylC₃-C₆cycloalkyl and R_(2a) is —CH₃. In another embodiment isa compound of Formula (IIa″), wherein R₂ is —CH₂—C₃-C₆cycloalkyl andR_(2a) is —CH₃. In another embodiment is a compound of Formula (IIa″),wherein R₂ is —C₁-C₆alkyl-CO₂R₆ and R_(2a) is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IIa″), wherein R₂ is—C₁-C₆alkyl-CO₂CH₃ and R_(2a) is —CH₃.

In another embodiment is a compound of Formula (IIa″), wherein X⁻ isCl⁻. In another embodiment is a compound of Formula (IIa″), wherein X⁻is Br⁻. In another embodiment is a compound of Formula (IIa″), whereinX⁻ is I⁻. In another embodiment is a compound of Formula (IIa″), whereinX⁻ is CF₃CO₂ ⁻. In another embodiment is a compound of Formula (IIa″),wherein X⁻ is Cl⁻, Br⁻, I⁻, or CF₃CO₂ ⁻.

In another embodiment is a compound of Formula (IIb):

wherein:X⁻ is a counterion;Z is a single bond, double bond, —CH₂—, or —O—;R₁ is aryl or heteroaryl, wherein aryl and heteroaryl are optionallysubstituted with one or more R₄;R_(2a) is C₁-C₆alkyl, —C₁-C₆alkyl-OR₅, or —C₁-C₆alkylC₃-C₆cycloalkyl;R₂ is C₁-C₆alkyl, —C₁-C₆alkyl-OR₆, —C₁-C₆alkylC₃-C₆cycloalkyl, or—C₁-C₆alkyl-CO₂R₆;R₃ and R₅ are each independently H, or C₁-C₆alkyl; orR₃ and R₅ together form an optionally substituted C₃-C₆cycloalkyl ring,optionally substituted C₂-C₇heterocycloalkyl ring, optionallysubstituted aryl ring, or an optionally substituted heteroaryl ring;each R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀,—N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₇heterocycloalkyl, aryl, andheteroaryl;R₆ is H, or C₁-C₆alkyl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, —C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl;R₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, —C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl;R₁₁ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, aryl, heteroaryl, —C₁-C₆alkylC₃-C₆cycloalkyl,—C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl;R₁₂ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, aryl, heteroaryl, —C₁-C₆alkylC₃-C₆cycloalkyl,—C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl; or R₁₁ and R₁₂ together withthe nitrogen to which they are attached form an optionally substitutedC₂-C₇heterocycloalkyl ring; andR₁₃ and R₁₄ are each independently H, or C₁-C₆alkyl;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In one embodiment is a compound of Formula (IIb), wherein R₁ is aryloptionally substituted with one or more R₄. In another embodiment is acompound of Formula (IIb), wherein R₁ is phenyl optionally substitutedwith one or more R₄. In another embodiment is a compound of Formula(IIb), wherein R₁ is phenyl substituted with one or more R₄, whereineach R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl.In another embodiment is a compound of Formula (IIb), wherein R₁ isphenyl substituted with one or more R₄, wherein each R₄ is independentlyselected F, Cl, Br, I, —CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, andC₁-C₆alkyl. In another embodiment is a compound of Formula (IIb),wherein R₁ is 4-chlorophenyl.

In another embodiment is a compound of Formula (IIb) wherein R₁ isheteroaryl optionally substituted with one or more R₄. In anotherembodiment is a compound of Formula (IIb), wherein R₁ is heteroarylsubstituted with one or more R₄, wherein each R₄ is independentlyselected from F, Cl, Br, I, —CN, —NO₂, —CF₃, —OR₉, —OCF₃, —NR₈R₉,—C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl. In another embodimentis a compound of Formula (IIb), wherein R₁ is heteroaryl substitutedwith one or more R₄, wherein each R₄ is independently selected F, Cl,Br, I, —CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, and C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIb), wherein heteroaryl ispyridyl.

In another embodiment is a compound of Formula (IIb) wherein R₁₁ and R₁₂are each C₁-C₆alkyl. In another embodiment is a compound of Formula(IIb) wherein R₁₁ and R₁₂ are each —CH₃. In another embodiment is acompound of Formula (IIb) wherein R₁₁ is H and R₁₂ is C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIb) wherein R₁₁ is H andR₁₂ is —CH₃. In another embodiment is a compound of Formula (IIb)wherein R₁₁ is H and R₁₂ is C₃-C₆cycloalkyl. In another embodiment is acompound of Formula (IIb) wherein R₁₁ is H and R₁₂ isC₁-C₆alkylC₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (IIb) wherein R₁₁ is H and R₁₂ is C₁-C₆alkylaryl. In anotherembodiment is a compound of Formula (IIb) wherein R₁₁ is H and R₁₂ isC₁-C₆alkylheteroaryl.

In another embodiment is a compound of Formula (IIb) wherein R₁₃ and R₁₄are each H. In another embodiment is a compound of Formula (IIb) whereinR₁₃ and R₁₄ are each —CH₃.

In another embodiment is a compound of Formula (IIb) wherein R₃ and R₅are each H. In another embodiment is a compound of Formula (IIb) whereinR₃ and R₅ are each —CH₃.

In another embodiment is a compound of Formula (IIb) wherein R₁₁ and R₁₂are each H.

In another embodiment is a compound of Formula (IIb), wherein R₂ isC₁-C₆alkyl. In a further embodiment is a compound of Formula (IIb),wherein R₂ is —CH₃. In another embodiment is a compound of Formula (II),wherein R₂ is —CH₂CH₃. In another embodiment is a compound of Formula(IIb), wherein R₂ is C₁-C₆alkyl-OR₆. In another embodiment is a compoundof Formula (IIb), wherein R₂ is C₁-C₆alkyl-OH. In another embodiment isa compound of Formula (IIb), wherein R₂ is C₁-C₆alkylC₃-C₆cycloalkyl. Inanother embodiment is a compound of Formula (IIb), wherein R₂ is—CH₂—C₃-C₆cycloalkyl. In another embodiment is a compound of Formula(IIb), wherein R₂ is —CH₂-cyclopropyl. In another embodiment is acompound of Formula (IIb), wherein R₂ is —CH₂-cyclobutyl. In anotherembodiment is a compound of Formula (IIb), wherein R₂ is—CH₂-cyclopentyl. In another embodiment is a compound of Formula (IIb),wherein R₂ is —CH₂— cyclohexyl. In another embodiment is a compound ofFormula (IIb), wherein R₂ is C₁-C₆alkyl-CO₂R₆. In another embodiment isa compound of Formula (IIb), wherein R₂ is C₁-C₆alkyl-CO₂CH₃. In anotherembodiment is a compound of Formula (IIb), wherein R₂ isC₁-C₆alkyl-CO₂CH₂CH₃.

In another embodiment is a compound of Formula (IIb), wherein R_(2a) isC₁-C₆alkyl. In a further embodiment is a compound of Formula (IIb),wherein R_(2a) is —CH₃. In another embodiment is a compound of Formula(IIb), wherein R_(2a) is —CH₂CH₃. In another embodiment is a compound ofFormula (IIb), wherein R_(2a) is C₁-C₆alkyl-OR₅. In another embodimentis a compound of Formula (IIb), wherein R_(2a) is C₁-C₆alkyl-OH. Inanother embodiment is a compound of Formula (IIb), wherein R_(2a) isC₁-C₆alkylC₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (IIb), wherein R_(2a) is —CH₂—C₃-C₆cycloalkyl. In anotherembodiment is a compound of Formula (IIb), wherein R_(2a) is—CH₂-cyclopropyl. In another embodiment is a compound of Formula (IIb),wherein R_(2a) is —CH₂-cyclobutyl. In another embodiment is a compoundof Formula (IIb), wherein R_(2a) is —CH₂-cyclopentyl. In anotherembodiment is a compound of Formula (IIb), wherein R_(2a) is—CH₂-cyclohexyl.

In another embodiment is a compound of Formula (IIb), wherein R₂ isC₁-C₆alkyl and R_(2a) is C₁-C₆alkyl. In another embodiment is a compoundof Formula (IIb), wherein R₂ is —CH₃ and R_(2a) is —CH₃. In anotherembodiment is a compound of Formula (IIb), wherein R₂ is —CH₂CH₃ andR_(2a) is —CH₃. In another embodiment is a compound of Formula (IIb),wherein R₂ is —C₁-C₆alkyl-OR₆ and R_(2a) is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IIb), wherein R₂ is —C₁-C₆alkyl-OHand R_(2a) is C₁-C₆alkyl. In another embodiment is a compound of Formula(IIb), wherein R₂ is —C₁-C₆alkyl-OH and R_(2a) is —CH₃. In anotherembodiment is a compound of Formula (IIb), wherein R₂ is—C₁-C₆alkylC₃-C₆cycloalkyl and R_(2a) is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IIb), wherein R₂ is—C₁-C₆alkylC₃-C₆cycloalkyl and R_(2a) is —CH₃. In another embodiment isa compound of Formula (IIb), wherein R₂ is —CH₂—C₃-C₆cycloalkyl andR_(2a) is —CH₃. In another embodiment is a compound of Formula (IIb),wherein R₂ is —C₁-C₆alkyl-CO₂R₆ and R_(2a) is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IIb), wherein R₂ is—C₁-C₆alkyl-CO₂CH₃ and R_(2a) is —CH₃.

In another embodiment is a compound of Formula (IIb), wherein Z is asingle bond. In another embodiment is a compound of Formula (IIb),wherein Z is a double bond. In another embodiment is a compound ofFormula (IIb), wherein Z is —CH₂—. In another embodiment is a compoundof Formula (IIb), wherein Z is —O—.

In another embodiment is a compound of Formula (IIb), wherein X⁻ is Cl⁻.In another embodiment is a compound of Formula (IIb), wherein X⁻ is Br⁻.In another embodiment is a compound of Formula (IIb), wherein X⁻ is I⁻.In another embodiment is a compound of Formula (IIb), wherein X⁻ isCF₃CO₂ ⁻. In another embodiment is a compound of Formula (IIb), whereinX is Cl⁻, Br⁻, I⁻, or CF₃CO₂ ⁻.

In another embodiment is a compound of Formula (IIb), having thestructure of Formula (IIb′):

wherein:X⁻ is a counterion;R₁ is aryl or heteroaryl, wherein aryl and heteroaryl are optionallysubstituted with one or more R₄;R_(2a) is C₁-C₆alkyl, —C₁-C₆alkyl-OR₅, or —C₁-C₆alkylC₃-C₆cycloalkyl;R₂ is C₁-C₆alkyl, —C₁-C₆alkyl-OR₆, —C₁-C₆alkylC₃-C₆cycloalkyl, or—C₁-C₆alkyl-CO₂R₆;each R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀,—N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₇heterocycloalkyl, aryl, andheteroaryl;R₅ is H, or C₁-C₆alkyl;R₆ is H, or C₁-C₆alkyl;R₈ is H, or C₁-C₆alkyl;R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, —C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl; andR₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, —C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In one embodiment is a compound of Formula (IIb′), wherein R₁ is aryloptionally substituted with one or more R₄. In another embodiment is acompound of Formula (IIb′), wherein R₁ is phenyl optionally substitutedwith one or more R₄. In another embodiment is a compound of Formula(IIb′), wherein R₁ is phenyl substituted with one or more R₄, whereineach R₄ is independently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl.In another embodiment is a compound of Formula (IIb′), wherein R₁ isphenyl substituted with one or more R₄, wherein each R₄ is independentlyselected F, Cl, Br, I, —CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, andC₁-C₆alkyl. In another embodiment is a compound of Formula (IIb′),wherein R₁ is 4-chlorophenyl.

In another embodiment is a compound of Formula (IIb′) wherein R₁ isheteroaryl optionally substituted with one or more R₄. In anotherembodiment is a compound of Formula (IIb′), wherein R₁ is heteroarylsubstituted with one or more R₄, wherein each R₄ is independentlyselected from F, Cl, Br, I, —CN, —NO₂, —CF₃, —OR₉, —OCF₃, —NR₈R₉,—C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl. In another embodimentis a compound of Formula (IIb′), wherein R₁ is heteroaryl substitutedwith one or more R₄, wherein each R₄ is independently selected F, Cl,Br, I, —CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉, and C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IIb′), wherein heteroarylis pyridyl.

In another embodiment is a compound of Formula (IIb′), wherein R₂ isC₁-C₆alkyl. In a further embodiment is a compound of Formula (IIb′),wherein R₂ is —CH₃. In another embodiment is a compound of Formula (II),wherein R₂ is —CH₂CH₃. In another embodiment is a compound of Formula(IIb′), wherein R₂ is C₁-C₆alkyl-OR₆. In another embodiment is acompound of Formula (IIb′), wherein R₂ is C₁-C₆alkyl-OH. In anotherembodiment is a compound of Formula (IIb′), wherein R₂ isC₁-C₆alkylC₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (IIb′), wherein R₂ is —CH₂—C₃-C₆cycloalkyl. In anotherembodiment is a compound of Formula (IIb′), wherein R₂ is—CH₂-cyclopropyl. In another embodiment is a compound of Formula (IIb′),wherein R₂ is —CH₂-cyclobutyl. In another embodiment is a compound ofFormula (IIb′), wherein R₂ is —CH₂-cyclopentyl. In another embodiment isa compound of Formula (IIb′), wherein R₂ is —CH₂— cyclohexyl. In anotherembodiment is a compound of Formula (IIb′), wherein R₂ isC₁-C₆alkyl-CO₂R₆. In another embodiment is a compound of Formula (IIb′),wherein R₂ is C₁-C₆alkyl-CO₂CH₃. In another embodiment is a compound ofFormula (IIb′), wherein R₂ is C₁-C₆alkyl-CO₂CH₂CH₃.

In another embodiment is a compound of Formula (IIb′), wherein R_(2a) isC₁-C₆alkyl. In a further embodiment is a compound of Formula (IIb′),wherein R_(2a) is —CH₃. In another embodiment is a compound of Formula(IIb′), wherein R_(2a) is —CH₂CH₃. In another embodiment is a compoundof Formula (IIb′), wherein R_(2a) is C₁-C₆alkyl-OR₅. In anotherembodiment is a compound of Formula (IIb′), wherein R_(2a) isC₁-C₆alkyl-OH. In another embodiment is a compound of Formula (IIb′),wherein R_(2a) is C₁-C₆alkylC₃-C₆cycloalkyl. In another embodiment is acompound of Formula (IIb′), wherein R_(2a) is —CH₂—C₃-C₆cycloalkyl. Inanother embodiment is a compound of Formula (IIb′), wherein R_(2a) is—CH₂-cyclopropyl. In another embodiment is a compound of Formula (IIb′),wherein R_(2a) is —CH₂-cyclobutyl. In another embodiment is a compoundof Formula (IIb′), wherein R_(2a) is —CH₂-cyclopentyl. In anotherembodiment is a compound of Formula (IIb′), wherein R_(2a) is—CH₂-cyclohexyl.

In another embodiment is a compound of Formula (IIb′), wherein R₂ isC₁-C₆alkyl and R_(2a) is C₁-C₆alkyl. In another embodiment is a compoundof Formula (IIb′), wherein R₂ is —CH₃ and R_(2a) is —CH₃. In anotherembodiment is a compound of Formula (IIb′), wherein R₂ is —CH₂CH₃ andR_(2a) is —CH₃. In another embodiment is a compound of Formula (IIb′),wherein R₂ is —C₁-C₆alkyl-OR₆ and R_(2a) is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IIb′), wherein R₂ is —C₁-C₆alkyl-OHand R_(2a) is C₁-C₆alkyl. In another embodiment is a compound of Formula(IIb′), wherein R₂ is —C₁-C₆alkyl-OH and R_(2a) is —CH₃. In anotherembodiment is a compound of Formula (IIb′), wherein R₂ is—C₁-C₆alkylC₃-C₆cycloalkyl and R_(2a) is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IIb′), wherein R₂ is—C₁-C₆alkylC₃-C₆cycloalkyl and R_(2a) is —CH₃. In another embodiment isa compound of Formula (IIb′), wherein R₂ is —CH₂—C₃-C₆cycloalkyl andR_(2a) is —CH₃. In another embodiment is a compound of Formula (IIb′),wherein R₂ is —C₁-C₆alkyl-CO₂R₆ and R_(2a) is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IIb′), wherein R₂ is—C₁-C₆alkyl-CO₂CH₃ and R_(2a) is —CH₃.

In another embodiment is a compound of Formula (IIb′), wherein X⁻ isCl⁻. In another embodiment is a compound of Formula (IIb′), wherein X⁻is Br⁻. In another embodiment is a compound of Formula (IIb′), whereinX⁻ is I⁻. In another embodiment is a compound of Formula (IIb′), whereinX⁻ is CF₃CO₂ ⁻. In another embodiment is a compound of Formula (IIb′),wherein X⁻ is Cl⁻, Br⁻, I⁻, or CF₃CO₂ ⁻.

In another embodiment is a compound of Formula (IIb), having thestructure of Formula (IIb″):

wherein:X⁻ is a counterion;R_(2a) is C₁-C₆alkyl;R₂ is C₁-C₆alkyl, —C₁-C₆alkyl-OR₆, —C₁-C₆alkylC₃-C₆cycloalkyl, or—C₁-C₆alkyl-CO₂R₆; andR₆ is H, or C₁-C₆alkyl;or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In one embodiment is a compound of Formula (IIb″), wherein R₂ isC₁-C₆alkyl. In a further embodiment is a compound of Formula (IIb″),wherein R₂ is —CH₃. In another embodiment is a compound of Formula(IIb″), wherein R₂ is —CH₂CH₃. In another embodiment is a compound ofFormula (IIb″), wherein R₂ is C₁-C₆alkyl-OR₆. In another embodiment is acompound of Formula (IIb″), wherein R₂ is C₁-C₆alkyl-OH. In anotherembodiment is a compound of Formula (IIb″), wherein R₂ isC₁-C₆alkylC₃-C₆cycloalkyl. In another embodiment is a compound ofFormula (IIb″), wherein R₂ is —CH₂—C₃-C₆cycloalkyl. In anotherembodiment is a compound of Formula (IIb″), wherein R₂ is—CH₂-cyclopropyl. In another embodiment is a compound of Formula (IIb″),wherein R₂ is —CH₂-cyclobutyl. In another embodiment is a compound ofFormula (IIb″), wherein R₂ is —CH₂-cyclopentyl. In another embodiment isa compound of Formula (IIb″), wherein R₂ is —CH₂— cyclohexyl. In anotherembodiment is a compound of Formula (IIb″), wherein R₂ isC₁-C₆alkyl-CO₂R₆. In another embodiment is a compound of Formula (IIb″),wherein R₂ is C₁-C₆alkyl-CO₂CH₃. In another embodiment is a compound ofFormula (IIb″), wherein R₂ is C₁-C₆alkyl-CO₂CH₂CH₃.

In another embodiment is a compound of Formula (IIb″), wherein R_(2a) isC₁-C₆alkyl. In a further embodiment is a compound of Formula (IIb″),wherein R_(2a) is —CH₃. In another embodiment is a compound of Formula(IIb″), wherein R_(2a) is —CH₂CH₃.

In another embodiment is a compound of Formula (IIb″), wherein R₂ isC₁-C₆alkyl and R_(2a) is C₁-C₆alkyl. In another embodiment is a compoundof Formula (IIb″), wherein R₂ is —CH₃ and R_(2a) is —CH₃. In anotherembodiment is a compound of Formula (IIb″), wherein R₂ is —CH₂CH₃ andR_(2a) is —CH₃. In another embodiment is a compound of Formula (IIb″),wherein R₂ is —C₁-C₆alkyl-OR₆ and R_(2a) is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IIb″), wherein R₂ is —C₁-C₆alkyl-OHand R_(2a) is C₁-C₆alkyl. In another embodiment is a compound of Formula(IIb″), wherein R₂ is —C₁-C₆alkyl-OH and R_(2a) is —CH₃. In anotherembodiment is a compound of Formula (IIb″), wherein R₂ is—C₁-C₆alkylC₃-C₆cycloalkyl and R_(2a) is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IIb″), wherein R₂ is—C₁-C₆alkylC₃-C₆cycloalkyl and R_(2a) is —CH₃. In another embodiment isa compound of Formula (IIb″), wherein R₂ is —CH₂—C₃-C₆cycloalkyl andR_(2a) is —CH₃. In another embodiment is a compound of Formula (IIb″),wherein R₂ is —C₁-C₆alkyl-CO₂R₆ and R_(2a) is C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IIb″), wherein R₂ is—C₁-C₆alkyl-CO₂CH₃ and R_(2a) is —CH₃.

In another embodiment is a compound of Formula (IIb″), wherein X⁻ isCl⁻. In another embodiment is a compound of Formula (IIb″), wherein X⁻is Br⁻. In another embodiment is a compound of Formula (IIb″), whereinX⁻ is I⁻. In another embodiment is a compound of Formula (IIb″), whereinX⁻ is CF₃CO₂ ⁻. In another embodiment is a compound of Formula (IIb″),wherein X⁻ is Cl⁻, Br⁻, I⁻, or CF₃CO₂ ⁻.

In some embodiments is a compound having the structure:

In some embodiments is a compound having the structure:

or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In some embodiments is a compound having the structure:

In some embodiments is a compound having the structure:

or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

In some embodiments is a compound having the structure:

In some embodiments is a compound having the structure:

or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.

Synthesis of Compounds

In some embodiments, the synthesis of compounds described herein areaccomplished using means described in the chemical literature, using themethods described herein, or by a combination thereof. In addition,solvents, temperatures and other reaction conditions presented hereinmay vary.

In other embodiments, the starting materials and reagents used for thesynthesis of the compounds described herein are synthesized or areobtained from commercial sources, such as, but not limited to,Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.

In further embodiments, the compounds described herein, and otherrelated compounds having different substituents are synthesized usingtechniques and materials described herein as well as those that arerecognized in the field, such as described, for example, in Fieser andFieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley andSons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989), March, Advanced OrganicChemistry 4^(th) Ed., (Wiley 1992); Carey and Sundberg, Advanced OrganicChemistry 4^(th) Ed., Vols. A and B (Plenum 2000, 2001), and Green andWuts, Protective Groups in Organic Synthesis 3^(rd) Ed., (Wiley 1999)(all of which are incorporated by reference for such disclosure).General methods for the preparation of compound as disclosed herein maybe derived from reactions and the reactions may be modified by the useof appropriate reagents and conditions, for the introduction of thevarious moieties found in the formulae as provided herein.

In some embodiments, described herein, the process for the preparationof(4R,7S)-2-(3-(4-chlorophenyl)ureido)-9-methyl-5,6,7,8-tetrahydro-4H-4,7-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride, is outlined in Scheme 1:

In another aspect, described herein, the process for the preparation of(4R,7S)-2-(3-(4-chlorophenyl)ureido)-9-methyl-5,6,7,8-tetrahydro-4H-4,7-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride, comprises:

A) the reaction of a compound with the structure

with sodium borohydride in the presence of a solvent to produce acompound with the structure

B) followed by the reaction of the compound with the structure

with pyridine and methanesulfonyl chloride in the presence of a solvent,followed by treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) toproduce a compound with the structure

C) followed by the reaction of the compound with the structure

with an aqueous base and then an acid to produce a compound with thestructure

D) followed by the reaction of the compound with the structure

with sodium carbonate, 4-dimethylaminopyridine (DMAP), and diphenylphosphoryl azide (DPPA) in the presence of a solvent followed bytreatment with an acid to produce a compound with the structure

E) followed by the reaction of the compound with the structure

with malononitrile, sulfur, and morpholine to produce a compound withthe structure

F) followed by the reaction of the compound with the structure

with concentrated sulfuric acid to produce a compound with the structure

G) followed by the reaction of the compound with the structure

with 4-chlorophenyl isocyanate in the presence of a solvent to produce acompound with the structure

H) followed by the reaction of the compound with the structure

with hydrochloric acid in the presence of a solvent produce(4R,7S)-2-(3-(4-chlorophenyl)ureido)-9-methyl-5,6,7,8-tetrahydro-4H-4,7-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride having the structure

In some embodiments of the process of Scheme 1, the base is selectedfrom MOH, M₂CO₃, and MHCO₃ wherein M is selected from lithium, sodium,potassium, and cesium; 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), R₁R₂R₃Nwherein R₁, R₂, and R₃ are each independently C₁-C₆alkyl. In someembodiments of the process of Scheme 1, the base is MOH. In someembodiments of the process of Scheme 1, the base is NaOH. In someembodiments of the process of Scheme 1, the base is KOH. In someembodiments of the process of Scheme 1, the base is1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). In some embodiments of theprocess of Scheme 1, the base is R₁R₂R₃N wherein R₁, R₂, and R₃ are eachindependently C₁-C₆alkyl. In some embodiments of the process of Scheme1, the base is R₁R₂R₃N wherein R₁, R₂, and R₃ are each ethyl. In someembodiments of the process of Scheme 1, the base is R₁R₂R₃N wherein R₁and R₂ are isopropyl and R₃ is ethyl.

In some embodiments of the process of Scheme 1, the acid is an inorganicacid. In some embodiments of the process of Scheme 1, the acid is aninorganic acid wherein the inorganic acid is hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, or metaphosphoricacid. In some embodiments of the process of Scheme 1, the acid is aninorganic acid wherein the inorganic acid is hydrochloric acid. In someembodiments of the process of Scheme 1, the acid is an inorganic acidwherein the inorganic acid is hydrobromic acid. In some embodiments ofthe process of Scheme 1, the acid is an inorganic acid wherein theinorganic acid is sulfuric acid. In some embodiments of the process ofScheme 1, the acid is an inorganic acid wherein the inorganic acid isphosphoric acid. In some embodiments of the process of Scheme 1, theacid is an inorganic acid wherein the inorganic acid is metaphosphoricacid.

In some embodiments of the process of Scheme 1, the acid is an organicacid. In some embodiments of the process of Scheme 1, the acid is anorganic acid, wherein the organic acid is acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, L-malic acid,maleic acid, oxalic acid, fumaric acid, trifluoroacetic acid, tartaricacid, L-tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonicacid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, butyric acid, phenylacetic acid,phenylbutyric acid, or valproic acid.

In some embodiments of the process of Scheme 1, the solvent is selectedfrom water, C₁-C₆alcohol, tetrahydrofuran, 2-methyltetrahyrofuran,toluene, dichloromethane, dichloroethane, and mixtures thereof. In someembodiments of the process of Scheme 1, the solvent is water. In someembodiments of the process of Scheme 1, the solvent is C₁-C₆alcohol. Insome embodiments of the process of Scheme 1, the solvent is methanol. Insome embodiments of the process of Scheme 1, the solvent is isopropanol.In some embodiments of the process of Scheme 1, the solvent istetrahydrofuran. In some embodiments of the process of Scheme 1, thesolvent is 2-methyltetrahyrofuran. In some embodiments of the process ofScheme 1, the solvent is toluene. In some embodiments of the process ofScheme 1, the solvent is dichloromethane. In some embodiments of theprocess of Scheme 1, the solvent is dichloroethane.

In some embodiments, described herein, the process for the preparationof(4R,7S)-2-(3-(4-chlorophenyl)ureido)-9-methyl-5,6,7,8-tetrahydro-4H-4,7-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride, is outlined in Scheme 2:

In another aspect, described herein, the process for the preparation of(4R,7S)-2-(3-(4-chlorophenyl)ureido)-9-methyl-5,6,7,8-tetrahydro-4H-4,7-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride, comprises:

A) the reaction of a compound with the structure

with sodium borohydride in the presence of a solvent to produce acompound with the structure

B) followed by the reaction of the compound with the structure

with pyridine and methanesulfonyl chloride in the presence of a solvent,followed by treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) toproduce a compound with the structure

C) followed by the reaction of the compound with the structure

with an aqueous base and then an acid to produce a compound with thestructure

D) followed by the reaction of the compound with the structure

with sodium carbonate, 4-dimethylaminopyridine (DMAP), and diphenylphosphoryl azide (DPPA) in the presence of a solvent followed bytreatment with an acid to produce a compound with the structure

E) followed by the reaction of the compound with the structure

with NCCH₂C(O)NH₂, sulfur, and morpholine to produce a compound with thestructure

F) followed by the reaction of the compound with the structure

with 4-chlorophenyl isocyanate in the presence of a solvent to produce acompound with the structure

G) followed by the reaction of the compound with the structure

with hydrochloric acid in the presence of a solvent produce(4R,7S)-2-(3-(4-chlorophenyl)ureido)-9-methyl-5,6,7,8-tetrahydro-4H-4,7-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride having the structure

In some embodiments of the process of Scheme 2, the base is selectedfrom MOH, M₂CO₃, and MHCO₃ wherein M is selected from lithium, sodium,potassium, and cesium; 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), R₁R₂R₃Nwherein R₁, R₂, and R₃ are each independently C₁-C₆alkyl. In someembodiments of the process of Scheme 2, the base is MOH. In someembodiments of the process of Scheme 2, the base is NaOH. In someembodiments of the process of Scheme 2, the base is KOH. In someembodiments of the process of Scheme 2, the base is1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). In some embodiments of theprocess of Scheme 2, the base is R₁R₂R₃N wherein R₁, R₂, and R₃ are eachindependently C₁-C₆alkyl. In some embodiments of the process of Scheme2, the base is R₁R₂R₃N wherein R₁, R₂, and R₃ are each ethyl. In someembodiments of the process of Scheme 2, the base is R₁R₂R₃N wherein R₁and R₂ are isopropyl and R₃ is ethyl.

In some embodiments of the process of Scheme 2, the acid is an inorganicacid. In some embodiments of the process of Scheme 2, the acid is aninorganic acid wherein the inorganic acid is hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, or metaphosphoricacid. In some embodiments of the process of Scheme 2, the acid is aninorganic acid wherein the inorganic acid is hydrochloric acid. In someembodiments of the process of Scheme 2, the acid is an inorganic acidwherein the inorganic acid is hydrobromic acid. In some embodiments ofthe process of Scheme 2, the acid is an inorganic acid wherein theinorganic acid is sulfuric acid. In some embodiments of the process ofScheme 2, the acid is an inorganic acid wherein the inorganic acid isphosphoric acid. In some embodiments of the process of Scheme 2, theacid is an inorganic acid wherein the inorganic acid is metaphosphoricacid.

In some embodiments of the process of Scheme 2, the acid is an organicacid. In some embodiments of the process of Scheme 2, the acid is anorganic acid, wherein the organic acid is acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, L-malic acid,maleic acid, oxalic acid, fumaric acid, trifluoroacetic acid, tartaricacid, L-tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonicacid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, butyric acid, phenylacetic acid,phenylbutyric acid, or valproic acid.

In some embodiments of the process of Scheme 2, the solvent is selectedfrom water, C₁-C₆alcohol, tetrahydrofuran, 2-methyltetrahyrofuran,toluene, dichloromethane, dichloroethane, and mixtures thereof. In someembodiments of the process of Scheme 2, the solvent is water. In someembodiments of the process of Scheme 2, the solvent is C₁-C₆alcohol. Insome embodiments of the process of Scheme 2, the solvent is methanol. Insome embodiments of the process of Scheme 2, the solvent is isopropanol.In some embodiments of the process of Scheme 2, the solvent istetrahydrofuran. In some embodiments of the process of Scheme 2, thesolvent is 2-methyltetrahyrofuran. In some embodiments of the process ofScheme 2, the solvent is toluene. In some embodiments of the process ofScheme 2, the solvent is dichloromethane. In some embodiments of theprocess of Scheme 2, the solvent is dichloroethane.

Use of Protecting Groups

In the reactions described, it may be necessary to protect reactivefunctional groups, for example hydroxy, amino, imino, thio or carboxygroups, where these are desired in the final product, in order to avoidtheir unwanted participation in reactions. Protecting groups are used toblock some or all of the reactive moieties and prevent such groups fromparticipating in chemical reactions until the protective group isremoved. It is preferred that each protective group be removable by adifferent means. Protective groups that are cleaved under totallydisparate reaction conditions fulfill the requirement of differentialremoval.

Protective groups are optionally removed by acid, base, reducingconditions (such as, for example, hydrogenolysis), and/or oxidativeconditions. Groups such as trityl, dimethoxytrityl, acetal andt-butyldimethylsilyl are acid labile and may be used to protect carboxyand hydroxy reactive moieties in the presence of amino groups protectedwith Cbz groups, which are removable by hydrogenolysis, and Fmoc groups,which are base labile. Carboxylic acid and hydroxy reactive moieties maybe blocked with base labile groups such as, but not limited to, methyl,ethyl, and acetyl in the presence of amines blocked with acid labilegroups such as t-butyl carbamate or with carbamates that are both acidand base stable but hydrolytically removable.

Carboxylic acid and hydroxy reactive moieties may also be blocked withhydrolytically removable protective groups such as the benzyl group,while amine groups capable of hydrogen bonding with acids may be blockedwith base labile groups such as Fmoc. Carboxylic acid reactive moietiesmay be protected by conversion to simple ester compounds as exemplifiedherein, which include conversion to alkyl esters, or they may be blockedwith oxidatively-removable protective groups such as2,4-dimethoxybenzyl, while co-existing amino groups may be blocked withfluoride labile silyl carbamates.

Allyl blocking groups are useful in then presence of acid- andbase-protecting groups since the former are stable and are optionallysubsequently removed by metal or pi-acid catalysts. For example, anallyl-blocked carboxylic acid are optionally deprotected with aPd⁰-catalyzed reaction in the presence of acid labile t-butyl carbamateor base-labile acetate amine protecting groups. Yet another form ofprotecting group is a resin to which a compound or intermediate may beattached. As long as the residue is attached to the resin, thatfunctional group is blocked and cannot react. Once released from theresin, the functional group is available to react.

Typically blocking/protecting groups may be selected from:

Other protecting groups, plus a detailed description of techniquesapplicable to the creation of protecting groups and their removal aredescribed in Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, N.Y., 1999, and Kocienski,Protective Groups, Thieme Verlag, New York, N.Y., 1994, which areincorporated herein by reference for such disclosure).

Pharmaceutical Compositions and Methods of Administration

Pharmaceutical compositions may be formulated in a conventional mannerusing one or more physiologically acceptable carriers includingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which are optionally used pharmaceutically.Proper formulation is dependent upon the route of administration chosen.Additional details about suitable excipients for pharmaceuticalcompositions described herein may be found, for example, in Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins, 1999), herein incorporatedby reference for such disclosure.

A pharmaceutical composition, as used herein, refers to a mixture of acompound of Formula (I), (Ia), (Ib), (II), (IIa), or (IIb) describedherein, with other chemical components, such as carriers, stabilizers,diluents, dispersing agents, suspending agents, thickening agents,and/or excipients. The pharmaceutical composition facilitatesadministration of the compound to an organism. In practicing the methodsof treatment or use provided herein, therapeutically effective amountsof compounds described herein are administered in a pharmaceuticalcomposition to a mammal having a disease, disorder, or condition to betreated. In some embodiments, the mammal is a human. A therapeuticallyeffective amount depends on the severity of the disease, the age andrelative health of the subject, the potency of the compound used andother factors. The compounds of Formula (I), (Ia), (Ib), (II), (IIa), or(IIb) are optionally used singly or in combination with one or moretherapeutic agents as components of mixtures (as in combinationtherapy).

The pharmaceutical formulations described herein are optionallyadministered to a subject by multiple administration routes, includingbut not limited to, oral, parenteral (e.g., intravenous, subcutaneous,intramuscular), intranasal, buccal, topical, rectal, or transdermaladministration routes. Moreover, the pharmaceutical compositionsdescribed herein, which include a compound of Formula (I), (Ia), (Ib),(II), (IIa), or (IIb) described herein, are optionally formulated intoany suitable dosage form, including but not limited to, aqueous oraldispersions, liquids, gels, syrups, elixirs, slurries, suspensions,aerosols, controlled release formulations, fast melt formulations,effervescent formulations, lyophilized formulations, tablets, powders,pills, dragees, capsules, delayed release formulations, extended releaseformulations, pulsatile release formulations, multiparticulateformulations, and mixed immediate release and controlled releaseformulations.

One may administer the compounds and/or compositions in a local ratherthan systemic manner, for example, via injection of the compounddirectly into an organ or tissue, often in a depot preparation orsustained release formulation. Such long acting formulations may beadministered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Furthermore, one mayadminister the drug in a targeted drug delivery system, for example, ina liposome coated with organ-specific antibody. The liposomes will betargeted to and taken up selectively by the organ. In addition, the drugmay be provided in the form of a rapid release formulation, in the formof an extended release formulation, or in the form of an intermediaterelease formulation.

Pharmaceutical compositions including a compound described herein may bemanufactured in a conventional manner, such as, by way of example only,by means of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

The pharmaceutical compositions will include at least one compound ofFormula (I), (Ia), (Ib), (II), (IIa), or (IIb) described herein, as anactive ingredient in free-acid or free-base form, or in apharmaceutically acceptable salt form. In addition, the methods andpharmaceutical compositions described herein include the use ofcrystalline forms (also known as polymorphs), as well as activemetabolites of these compounds having the same type of activity. In somesituations, compounds may exist as tautomers. All tautomers are includedwithin the scope of the compounds presented herein. Additionally, manyof the compounds described herein exist in unsolvated as well assolvated forms with pharmaceutically acceptable solvents such as water,ethanol, and the like. The solvated forms of the compounds presentedherein are also considered to be disclosed herein.

In certain embodiments, compositions provided herein may also includeone or more preservatives to inhibit microbial activity. Suitablepreservatives include quaternary ammonium compounds such as benzalkoniumchloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

Pharmaceutical preparations for oral use are optionally obtained bymixing one or more solid excipient with one or more of the compounds ofFormula (I), (Ia), (Ib), (II), (IIa), or (IIb) described herein,optionally grinding the resulting mixture, and processing the mixture ofgranules, after adding suitable auxiliaries, if desired, to obtaintablets, pills, or capsules. Suitable excipients include, for example,fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Ifdesired, disintegrating agents may be added, such as the cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations that are used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules optionally contain the active ingredients in admixture withfiller such as lactose, binders such as starches, and/or lubricants suchas talc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added.

In some embodiments, the solid dosage forms disclosed herein may be inthe form of a tablet, (including a suspension tablet, a fast-melttablet, a bite-disintegration tablet, a rapid-disintegration tablet, aneffervescent tablet, or a caplet), a pill, a powder (including a sterilepackaged powder, a dispensable powder, or an effervescent powder), acapsule (including both soft or hard capsules, e.g., capsules made fromanimal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”),solid dispersion, solid solution, bioerodible dosage form, controlledrelease formulations, pulsatile release dosage forms, multiparticulatedosage forms, pellets, granules, or an aerosol. In other embodiments,the pharmaceutical formulation is in the form of a powder. In stillother embodiments, the pharmaceutical formulation is in the form of atablet, including but not limited to, a fast-melt tablet. Additionally,pharmaceutical formulations of the compounds described herein may beadministered as a single capsule or in multiple capsule dosage form. Insome embodiments, the pharmaceutical formulation is administered in two,or three, or four, capsules or tablets.

In some embodiments, solid dosage forms, e.g., tablets, effervescenttablets, and capsules, are prepared by mixing particles of a compound ofFormula (I), (Ia), (Ib), (II), (IIa), or (IIb) described herein, withone or more pharmaceutical excipients to form a bulk blend composition.When referring to these bulk blend compositions as homogeneous, it ismeant that the particles of the compound of Formula (I), (Ia), (Ib),(II), (IIa), or (IIb) described herein, are dispersed evenly throughoutthe composition so that the composition may be subdivided into equallyeffective unit dosage forms, such as tablets, pills, and capsules. Theindividual unit dosages may also include film coatings, whichdisintegrate upon oral ingestion or upon contact with diluent. Theseformulations are optionally manufactured by conventional pharmacologicaltechniques.

The pharmaceutical solid dosage forms described herein include acompound of Formula (I), (Ia), (Ib), (II), (IIa), or (IIb) describedherein, and optionally one or more pharmaceutically acceptable additivessuch as a compatible carrier, binder, filling agent, suspending agent,flavoring agent, sweetening agent, disintegrating agent, dispersingagent, surfactant, lubricant, colorant, diluent, solubilizer, moisteningagent, plasticizer, stabilizer, penetration enhancer, wetting agent,anti-foaming agent, antioxidant, preservative, or one or morecombination thereof. In still other aspects, using standard coatingprocedures, such as those described in Remington's PharmaceuticalSciences, 20th Edition (2000), a film coating is provided around theformulation of the compound described herein. In one embodiment, some orall of the particles of the compound described herein are coated. Inanother embodiment, some or all of the particles of the compounddescribed herein are microencapsulated. In still another embodiment, theparticles of the compound described herein are not microencapsulated andare uncoated.

Suitable carriers for use in the solid dosage forms described hereininclude, but are not limited to, acacia, gelatin, colloidal silicondioxide, calcium glycerophosphate, calcium lactate, maltodextrin,glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodiumchloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyllactylate, carrageenan, monoglyceride, diglyceride, pregelatinizedstarch, hydroxypropylmethylcellulose, hydroxypropylmethylcelluloseacetate stearate, sucrose, microcrystalline cellulose, lactose, mannitoland the like.

Suitable filling agents for use in the solid dosage forms describedherein include, but are not limited to, lactose, calcium carbonate,calcium phosphate, dibasic calcium phosphate, calcium sulfate,microcrystalline cellulose, cellulose powder, dextrose, dextrates,dextran, starches, pregelatinized starch, hydroxypropylmethycellulose(HPMC), hydroxypropylmethycellulose phthalate,hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose,xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethyleneglycol, and the like.

In order to release the compound of Formula (I), (Ia), (Ib), (II),(IIa), or (IIb) from a solid dosage form matrix as efficiently aspossible, disintegrants are often used in the formulation, especiallywhen the dosage forms are compressed with binder. Disintegrants helprupturing the dosage form matrix by swelling or capillary action whenmoisture is absorbed into the dosage form. Suitable disintegrants foruse in the solid dosage forms described herein include, but are notlimited to, natural starch such as corn starch or potato starch, apregelatinized starch such as National 1551 or Amijel®, or sodium starchglycolate such as Promogel® or Explotab®, a cellulose such as a woodproduct, methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101,Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, MingTia®, and Solka-Floc®, methylcellulose, croscarmellose, or across-linked cellulose, such as cross-linked sodiumcarboxymethylcellulose (Ac-Di-Sol®), cross-linkedcarboxymethylcellulose, or cross-linked croscarmellose, a cross-linkedstarch such as sodium starch glycolate, a cross-linked polymer such ascrospovidone, a cross-linked polyvinylpyrrolidone, alginate such asalginic acid or a salt of alginic acid such as sodium alginate, a claysuch as Veegum® HV (magnesium aluminum silicate), a gum such as agar,guar, locust bean, Karaya, pectin, or tragacanth, sodium starchglycolate, bentonite, a natural sponge, a surfactant, a resin such as acation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium laurylsulfate in combination starch, and the like.

Binders impart cohesiveness to solid oral dosage form formulations: forpowder filled capsule formulation, they aid in plug formation that areoptionally filled into soft or hard shell capsules and for tabletformulation, they ensure the tablet remaining intact after compressionand help assure blend uniformity prior to a compression or fill step.Materials suitable for use as binders in the solid dosage formsdescribed herein include, but are not limited to,carboxymethylcellulose, methylcellulose (e.g., Methocel®),hydroxypropylmethylcellulose (e.g. Hypromellose USP Pharmacoat-603,hydroxypropylmethylcellulose acetate stearate (Aqoate HS-LF and HS),hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®),ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g.,Avicel®), microcrystalline dextrose, amylose, magnesium aluminumsilicate, polysaccharide acids, bentonites, gelatin,polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone, povidone,starch, pregelatinized starch, tragacanth, dextrin, a sugar, such assucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol,xylitol (e.g., Xylitab®), lactose, a natural or synthetic gum such asacacia, tragacanth, ghatti gum, mucilage of isapol husks, starch,polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone®XL-10, and Povidone® K-12), larch arabogalactan, Veegum®, polyethyleneglycol, waxes, sodium alginate, and the like.

In general, binder levels of 20-70% are used in powder-filled gelatincapsule formulations. Binder usage level in tablet formulations varieswhether direct compression, wet granulation, roller compaction, or usageof other excipients such as fillers which itself can act as moderatebinder. In some embodiments, formulators determine the binder level forthe formulations, but binder usage level of up to 70% in tabletformulations is common.

Suitable lubricants or glidants for use in the solid dosage formsdescribed herein include, but are not limited to, stearic acid, calciumhydroxide, talc, corn starch, sodium stearyl fumerate, alkali-metal andalkaline earth metal salts, such as aluminum, calcium, magnesium, zinc,stearic acid, sodium stearates, magnesium stearate, zinc stearate,waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodiumchloride, leucine, a polyethylene glycol or a methoxypolyethylene glycolsuch as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol,sodium oleate, glyceryl behenate, glyceryl palmitostearate, glycerylbenzoate, magnesium or sodium lauryl sulfate, and the like.

Suitable diluents for use in the solid dosage forms described hereininclude, but are not limited to, sugars (including lactose, sucrose, anddextrose), polysaccharides (including dextrates and maltodextrin),polyols (including mannitol, xylitol, and sorbitol), cyclodextrins andthe like.

Suitable wetting agents for use in the solid dosage forms describedherein include, for example, oleic acid, glyceryl monostearate, sorbitanmonooleate, sorbitan monolaurate, triethanolamine oleate,polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitanmonolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodiumoleate, sodium lauryl sulfate, magnesium stearate, sodium docusate,triacetin, vitamin E TPGS and the like.

Suitable surfactants for use in the solid dosage forms described hereininclude, for example, sodium lauryl sulfate, sorbitan monooleate,polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bilesalts, glyceryl monostearate, copolymers of ethylene oxide and propyleneoxide, e.g., Pluronic® (BASF), and the like.

Suitable suspending agents for use in the solid dosage forms describedhere include, but are not limited to, polyvinylpyrrolidone, e.g.,polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidoneK25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., thepolyethylene glycol optionally is selected to have a molecular weight ofabout 300 to about 6000, or about 3350 to about 4000, or about 5400 toabout 7000, vinyl pyrrolidone/vinyl acetate copolymer (S630), sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as,e.g., gum tragacanth and gum acacia, guar gum, xanthans, includingxanthan gum, sugars, cellulosics, such as, e.g., sodiumcarboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80,sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylatedsorbitan monolaurate, povidone and the like.

Suitable antioxidants for use in the solid dosage forms described hereininclude, for example, e.g., butylated hydroxytoluene (BHT), sodiumascorbate, and tocopherol.

There is considerable overlap between additives used in the solid dosageforms described herein. Thus, the above-listed additives should be takenas merely exemplary, and not limiting, of the types of additives thatcan be included in solid dosage forms of the pharmaceutical compositionsdescribed herein.

In other embodiments, one or more layers of the pharmaceuticalformulation are plasticized. Illustratively, a plasticizer is generallya high boiling point solid or liquid. Suitable plasticizers can be addedfrom about 0.01% to about 50% by weight (w/w) of the coatingcomposition. Plasticizers include, but are not limited to, diethylphthalate, citrate esters, polyethylene glycol, glycerol, acetylatedglycerides, triacetin, polypropylene glycol, polyethylene glycol,triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, andcastor oil.

Compressed tablets are solid dosage forms prepared by compacting thebulk blend of the formulations described above. In various embodiments,compressed tablets which are designed to dissolve in the mouth willinclude one or more flavoring agents. In other embodiments, thecompressed tablets will include a film surrounding the final compressedtablet. In some embodiments, the film coating can provide a delayedrelease of the compounds of Formula (I) described herein from theformulation. In other embodiments, the film coating aids in patientcompliance (e.g., Opadry® coatings or sugar coating). Film coatingsincluding Opadry® typically range from about 1% to about 3% of thetablet weight. In other embodiments, the compressed tablets include oneor more excipients.

A capsule may be prepared, for example, by placing the bulk blend of theformulation of the compound described above, inside of a capsule. Insome embodiments, the formulations (non-aqueous suspensions andsolutions) are placed in a soft gelatin capsule. In other embodiments,the formulations are placed in standard gelatin capsules or non-gelatincapsules such as capsules comprising HPMC. In other embodiments, theformulation is placed in a sprinkle capsule, wherein the capsule may beswallowed whole or the capsule may be opened and the contents sprinkledon food prior to eating. In some embodiments, the therapeutic dose issplit into multiple (e.g., two, three, or four) capsules. In someembodiments, the entire dose of the formulation is delivered in acapsule form.

In various embodiments, the particles of the compound of Formula (I)described herein and one or more excipients are dry blended andcompressed into a mass, such as a tablet, having a hardness sufficientto provide a pharmaceutical composition that substantially disintegrateswithin less than about 30 minutes, less than about 35 minutes, less thanabout 40 minutes, less than about 45 minutes, less than about 50minutes, less than about 55 minutes, or less than about 60 minutes,after oral administration, thereby releasing the formulation into thegastrointestinal fluid.

In another aspect, dosage forms may include microencapsulatedformulations. In some embodiments, one or more other compatiblematerials are present in the microencapsulation material. Exemplarymaterials include, but are not limited to, pH modifiers, erosionfacilitators, anti-foaming agents, antioxidants, flavoring agents, andcarrier materials such as binders, suspending agents, disintegrationagents, filling agents, surfactants, solubilizers, stabilizers,lubricants, wetting agents, and diluents.

Microencapsulated compounds described herein may be formulated bymethods that include, e.g., spray drying processes, spinningdisk-solvent processes, hot melt processes, spray chilling methods,fluidized bed, electrostatic deposition, centrifugal extrusion,rotational suspension separation, polymerization at liquid-gas orsolid-gas interface, pressure extrusion, or spraying solvent extractionbath. In addition to these, several chemical techniques, e.g., complexcoacervation, solvent evaporation, polymer-polymer incompatibility,interfacial polymerization in liquid media, in situ polymerization,in-liquid drying, and desolvation in liquid media could also be used.Furthermore, other methods such as roller compaction,extrusion/spheronization, coacervation, or nanoparticle coating may alsobe used.

The pharmaceutical solid oral dosage forms including formulationsdescribed herein, which include a compound described herein, can befurther formulated to provide a controlled release of the compound ofFormula (I). Controlled release refers to the release of the compoundsdescribed herein from a dosage form in which it is incorporatedaccording to a desired profile over an extended period of time.Controlled release profiles include, for example, sustained release,prolonged release, pulsatile release, and delayed release profiles. Incontrast to immediate release compositions, controlled releasecompositions allow delivery of an agent to a subject over an extendedperiod of time according to a predetermined profile. Such release ratescan provide therapeutically effective levels of agent for an extendedperiod of time and thereby provide a longer period of pharmacologicresponse while minimizing side effects as compared to conventional rapidrelease dosage forms. Such longer periods of response provide for manyinherent benefits that are not achieved with the corresponding shortacting, immediate release preparations.

In other embodiments, the formulations described herein, which include acompound of Formula (I) described herein, are delivered using apulsatile dosage form. A pulsatile dosage form is capable of providingone or more immediate release pulses at predetermined time points aftera controlled lag time or at specific sites. Pulsatile dosage forms maybe administered using a variety of pulsatile formulations including, butare not limited to, those described in U.S. Pat. Nos. 5,011,692;5,017,381; 5,229,135; 5,840,329; 4,871,549; 5,260,068; 5,260,069;5,508,040; 5,567,441 and 5,837,284.

Many other types of controlled release systems are suitable for use withthe formulations described herein. Examples of such delivery systemsinclude, e.g., polymer-based systems, such as polylactic andpolyglycolic acid, polyanhydrides and polycaprolactone; porous matrices,nonpolymer-based systems that are lipids, including sterols, such ascholesterol, cholesterol esters and fatty acids, or neutral fats, suchas mono-, di- and triglycerides; hydrogel release systems; silasticsystems; peptide-based systems; wax coatings, bioerodible dosage forms,compressed tablets using conventional binders and the like. See, e.g.,Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214(1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2ndEd., pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725; 4,624,848; 4,968,509;5,461,140; 5,456,923; 5,516,527; 5,622,721; 5,686,105; 5,700,410;5,977,175; 6,465,014; and 6,932,983.

In some embodiments, pharmaceutical formulations are provided thatinclude particles of the compounds described herein, e.g. compounds ofFormula (I), and at least one dispersing agent or suspending agent fororal administration to a subject. The formulations may be a powderand/or granules for suspension, and upon admixture with water, asubstantially uniform suspension is obtained.

Liquid formulation dosage forms for oral administration can be aqueoussuspensions selected from the group including, but not limited to,pharmaceutically acceptable aqueous oral dispersions, emulsions,solutions, elixirs, gels, and syrups. See, e.g., Singh et al.,Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002).

The aqueous suspensions and dispersions described herein can remain in ahomogenous state, as defined in The USP Pharmacists' Pharmacopeia (2005edition, chapter 905), for at least 4 hours. The homogeneity should bedetermined by a sampling method consistent with regard to determininghomogeneity of the entire composition. In one embodiment, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 1 minute. In another embodiment, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 45 seconds. In yet another embodiment, anaqueous suspension can be re-suspended into a homogenous suspension byphysical agitation lasting less than 30 seconds. In still anotherembodiment, no agitation is necessary to maintain a homogeneous aqueousdispersion.

The pharmaceutical compositions described herein may include sweeteningagents such as, but not limited to, acacia syrup, acesulfame K, alitame,anise, apple, aspartame, banana, Bavarian cream, berry, black currant,butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream,chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream,cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate,cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger,glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey,isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate(MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mintcream, mixed berry, neohesperidine DC, neotame, orange, pear, peach,peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer,rum, saccharin, safrole, sorbitol, spearmint, spearmint cream,strawberry, strawberry cream, stevia, sucralose, sucrose, sodiumsaccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin,sucralose, sorbitol, swiss cream, tagatose, tangerine, thaumatin, tuttifruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol,or any combination of these flavoring ingredients, e.g., anise-menthol,cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint,honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream,vanilla-mint, and mixtures thereof.

For intravenous injections, compounds described herein may be formulatedin aqueous solutions, preferably in physiologically compatible bufferssuch as Hank's solution, Ringer's solution, or physiological salinebuffer. For transmucosal administration, penetrants appropriate to thebarrier to be permeated are used in the formulation. Such penetrants aregenerally recognized in the field. For other parenteral injections,appropriate formulations may include aqueous or nonaqueous solutions,preferably with physiologically compatible buffers or excipients. Suchexcipients are generally recognized in the field.

Parenteral injections may involve bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosageform, e.g., in ampoules or in multi-dose containers, with an addedpreservative. The pharmaceutical composition described herein may be ina form suitable for parenteral injection as a sterile suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. Pharmaceutical formulations for parenteral administrationinclude aqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

In certain embodiments, delivery systems for pharmaceutical compoundsmay be employed, such as, for example, liposomes and emulsions. Incertain embodiments, compositions provided herein also include anmucoadhesive polymer, selected from among, for example,carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

Generally, an agent, such as a compound of Formula (I), is administeredin an amount effective for amelioration of, or prevention of thedevelopment of symptoms of, the disease or disorder (i.e., atherapeutically effective amount). Thus, a therapeutically effectiveamount can be an amount that is capable of at least partially preventingor reversing a disease or disorder. The dose required to obtain aneffective amount may vary depending on the agent, formulation, diseaseor disorder, and individual to whom the agent is administered.

Determination of effective amounts may also involve in vitro assays inwhich varying doses of agent are administered to cells in culture andthe concentration of agent effective for ameliorating some or allsymptoms is determined in order to calculate the concentration requiredin vivo. Effective amounts may also be based in in vivo animal studies.

An agent can be administered prior to, concurrently with and subsequentto the appearance of symptoms of a disease or disorder. In someembodiments, an agent is administered to a subject with a family historyof the disease or disorder, or who has a phenotype that may indicate apredisposition to a disease or disorder, or who has a genotype whichpredisposes the subject to the disease or disorder.

Methods of Dosing and Treatment Regimens

The compositions containing the compound(s) described herein can beadministered for prophylactic and/or therapeutic treatments. Intherapeutic applications, the compositions are administered to a patientalready suffering from a disease or condition, in an amount sufficientto cure or at least partially arrest the symptoms of the disease orcondition. Amounts effective for this use will depend on the severityand course of the disease or condition, previous therapy, the patient'shealth status, weight, and response to the drugs, and the judgment ofthe treating physician.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in a patient, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician.

In the case wherein the patient's condition does not improve, upon thedoctor's discretion the administration of the compounds may beadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disease, disorder orcondition is retained. Patients can, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, disease orcondition and its severity, the identity (e.g., weight) of the subjector host in need of treatment, but can nevertheless be determined in amanner recognized in the field according to the particular circumstancessurrounding the case, including, e.g., the specific agent beingadministered, the route of administration, the condition being treated,and the subject or host being treated. In general, however, dosesemployed for adult human treatment will typically be in the range ofabout 0.02-about 5000 mg per day, in some embodiments, about 1-about1500 mg per day. The desired dose may conveniently be presented in asingle dose or as divided doses administered simultaneously (or over ashort period of time) or at appropriate intervals, for example as two,three, four or more sub-doses per day.

The pharmaceutical composition described herein may be in unit dosageforms suitable for single administration of precise dosages. In unitdosage form, the formulation is divided into unit doses containingappropriate quantities of one or more compound. The unit dosage may bein the form of a package containing discrete quantities of theformulation. Non-limiting examples are packaged tablets or capsules, andpowders in vials or ampoules. Aqueous suspension compositions can bepackaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers can be used, in which case it istypical to include a preservative in the composition. By way of exampleonly, formulations for parenteral injection may be presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

The daily dosages appropriate for the compounds described herein arefrom about 0.01 mg/kg to about 20 mg/kg. In one embodiment, the dailydosages are from about 0.1 mg/kg to about 10 mg/kg. An indicated dailydosage in the larger mammal, including, but not limited to, humans, isin the range from about 0.5 mg to about 1000 mg, convenientlyadministered in a single dose or in divided doses, including, but notlimited to, up to four times a day or in extended release form. Suitableunit dosage forms for oral administration include from about 1 to about500 mg active ingredient. In one embodiment, the unit dosage is about 1mg, about 5 mg, about, 10 mg, about 20 mg, about 50 mg, about 100 mg,about 200 mg, about 250 mg, about 400 mg, or about 500 mg. The foregoingranges are merely suggestive, as the number of variables in regard to anindividual treatment regime is large, and considerable excursions fromthese recommended values are not uncommon. Such dosages may be altereddepending on a number of variables, not limited to the activity of thecompound used, the disease or condition to be treated, the mode ofadministration, the requirements of the individual subject, the severityof the disease or condition being treated, and the judgment of thepractitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD₅₀ and ED₅₀. Compoundsexhibiting high therapeutic indices are preferred. The data obtainedfrom cell culture assays and animal studies can be used in formulating arange of dosage for use in human. The dosage of such compounds liespreferably within a range of circulating concentrations that include theED₅₀ with minimal toxicity. The dosage may vary within this rangedepending upon the dosage form employed and the route of administrationutilized.

Combination Treatments

The compounds of Formula (I), (Ia), (Ib), (II), (IIa), or (IIb)described herein, and compositions thereof, may also be used incombination with other therapeutic agents that are selected for theirtherapeutic value for the condition to be treated. In general, thecompositions described herein and, in embodiments where combinationaltherapy is employed, other agents do not have to be administered in thesame pharmaceutical composition, and may, because of different physicaland chemical characteristics, have to be administered by differentroutes. The determination of the mode of administration and theadvisability of administration, where possible, in the samepharmaceutical composition, is well within the knowledge of theclinician. The initial administration can be made according toestablished protocols recognized in the field, and then, based upon theobserved effects, the dosage, modes of administration and times ofadministration can be modified by the clinician.

In certain instances, it may be appropriate to administer at least onecompound described herein in combination with another therapeutic agent.By way of example only, if one of the side effects experienced by apatient upon receiving one of the compounds herein, such as a compoundof Formula (I), is nausea, then it may be appropriate to administer ananti-nausea agent in combination with the initial therapeutic agent. Or,by way of example only, the therapeutic effectiveness of one of thecompounds described herein may be enhanced by administration of anadjuvant (i.e., by itself the adjuvant may have minimal therapeuticbenefit, but in combination with another therapeutic agent, the overalltherapeutic benefit to the patient is enhanced). Or, by way of exampleonly, the benefit experienced by a patient may be increased byadministering one of the compounds described herein with anothertherapeutic agent (which also includes a therapeutic regimen) that alsohas therapeutic benefit. In any case, regardless of the disease,disorder or condition being treated, the overall benefit experienced bythe patient may simply be additive of the two therapeutic agents or thepatient may experience a synergistic benefit.

In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa),or (IIb) is administered in combination with an aminoglycosideantibiotic. In some embodiments, a compound of Formula (I), (Ia), (Ib),(II), (IIa), or (IIb) is administered in combination with anaminoglycoside antibiotic selected from streptomycin, neomycin,framycetin, paromomycin, paromomycin sulfate, ribostamycin, kanamycin,amikacin, arbekacin, bekanamycin, dibekacin, tobramycin, spectinomycin,hygromycin B, gentamicin, netilmicin, sisomicin, isepamicin, verdamicin,and astromicin. In some embodiments, a compound of Formula (I), (Ia),(Ib), (II), (IIa), or (IIb) is administered in combination withstreptomycin. In some embodiments, a compound of Formula (I), (Ia),(Ib), (II), (IIa), or (IIb) is administered in combination withamikacin. In some embodiments, a compound of Formula (I), (Ia), (Ib),(II), (IIa), or (IIb) is administered in combination with neomycin. Insome embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), or(IIb) is administered in combination with kanamycin. In someembodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), or(IIb) is administered in combination with gentamicin. In someembodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa), or(IIb) is administered in combination with tobramycin.

In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa),or (IIb) is administered for 1-7 days, and then the compound of Formula(I), (Ia), (Ib), (II), (IIa), or (IIb) is administered in combinationwith an aminoglycoside antibiotic. In some embodiments, a compound ofFormula (I), (Ia), (Ib), (II), (IIa), or (IIb) is administered for 7days, and then the compound of Formula (I), (Ia), (Ib), (II), (IIa), or(IIb) is administered in combination with an aminoglycoside antibiotic.In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa),or (IIb) is administered for 6 days, and then the compound of Formula(I), (Ia), (Ib), (II), (IIa), or (IIb) is administered in combinationwith an aminoglycoside antibiotic. In some embodiments, a compound ofFormula (I), (Ia), (Ib), (II), (IIa), or (IIb) is administered for 5days, and then the compound of Formula (I), (Ia), (Ib), (II), (IIa), or(IIb) is administered in combination with an aminoglycoside antibiotic.In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa),or (IIb) is administered for 4 days, and then the compound of Formula(I), (Ia), (Ib), (II), (IIa), or (IIb) is administered in combinationwith an aminoglycoside antibiotic. In some embodiments, a compound ofFormula (I), (Ia), (Ib), (II), (IIa), or (IIb) is administered for 3days, and then the compound of Formula (I), (Ia), (Ib), (II), (IIa), or(IIb) is administered in combination with an aminoglycoside antibiotic.In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa),or (IIb) is administered for 2 days, and then the compound of Formula(I), (Ia), (Ib), (II), (IIa), or (IIb) is administered in combinationwith an aminoglycoside antibiotic. In some embodiments, a compound ofFormula (I), (Ia), (Ib), (II), (IIa), or (IIb) is administered for 1day, and then the compound of Formula (I), (Ia), (Ib), (II), (IIa), or(IIb) is administered in combination with an aminoglycoside antibiotic.In some embodiments, the compound of Formula (I), (Ia), (Ib), (II),(IIa), or (IIb) is administered an additional 7 days following theadministration of the aminoglycoside antibiotic. In some embodiments,the compound of Formula (I), (Ia), (Ib), (II), (IIa), or (IIb) isadministered an additional 6 days following the administration of theaminoglycoside antibiotic. In some embodiments, the compound of Formula(I), (Ia), (Ib), (II), (IIa), or (IIb) is administered an additional 5days following the administration of the aminoglycoside antibiotic. Insome embodiments, the compound of Formula (I), (Ia), (Ib), (II), (IIa),or (IIb) is administered an additional 4 days following theadministration of the aminoglycoside antibiotic. In some embodiments,the compound of Formula (I), (Ia), (Ib), (II), (IIa), or (IIb) isadministered an additional 3 days following the administration of theaminoglycoside antibiotic. In some embodiments, the compound of Formula(I), (Ia), (Ib), (II), (IIa), or (IIb) is administered an additional 2days following the administration of the aminoglycoside antibiotic. Insome embodiments, the compound of Formula (I), (Ia), (Ib), (II), (IIa),or (IIb) is administered an additional 1 day following theadministration of the aminoglycoside antibiotic.

In some embodiments the compound of Formula (I), (Ia), (Ib), (II),(IIa), or (IIb) and the aminoglycoside antibiotic are administered incombination in a single dosage form. In some embodiments the compound ofFormula (I), (Ia), (Ib), (II), (IIa), or (IIb) and the aminoglycosideantibiotic are administered in combination in separate dosage forms.

In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa),or (IIb) is administered in combination with a chemotherapeutic agent.In some embodiments, a compound of Formula (I), (Ia), (Ib), (II), (IIa),or (IIb) is administered in combination with a chemotherapeutic agentselected from cisplatin and carboplatin. In some embodiments, a compoundof Formula (I), (Ia), (Ib), (II), (IIa), or (IIb) is administered incombination with cisplatin. In some embodiments, a compound of Formula(I), (Ia), (Ib), (II), (IIa), or (IIb) is administered in combinationwith carboplatin.

The particular choice of compounds used will depend upon the diagnosisof the attending physicians and their judgment of the condition of thepatient and the appropriate treatment protocol. The compounds may beadministered concurrently (e.g., simultaneously, essentiallysimultaneously or within the same treatment protocol) or sequentially,depending upon the nature of the disease, disorder, or condition, thecondition of the patient, and the actual choice of compounds used. Thedetermination of the order of administration, and the number ofrepetitions of administration of each therapeutic agent during atreatment protocol, is well within the knowledge of the physician afterevaluation of the disease being treated and the condition of thepatient.

Therapeutically-effective dosages can vary when the drugs are used intreatment combinations. Methods for experimentally determiningtherapeutically-effective dosages of drugs and other agents for use incombination treatment regimens are described in the literature. Forexample, the use of metronomic dosing, i.e., providing more frequent,lower doses in order to minimize toxic side effects, has been describedextensively in the literature Combination treatment further includesperiodic treatments that start and stop at various times to assist withthe clinical management of the patient.

For combination therapies described herein, dosages of theco-administered compounds will of course vary depending on the type ofco-drug employed, on the specific drug employed, on the disease orcondition being treated and so forth. In addition, when co-administeredwith one or more biologically active agents, the compound providedherein may be administered either simultaneously with the biologicallyactive agent(s), or sequentially. If administered sequentially, theattending physician will decide on the appropriate sequence ofadministering protein in combination with the biologically activeagent(s).

In any case, the multiple therapeutic agents (one of which is a compoundof Formula (I), (Ia), (Ib), (II), (IIa), or (IIb) described herein) maybe administered in any order or even simultaneously. If simultaneously,the multiple therapeutic agents may be provided in a single, unifiedform, or in multiple forms (by way of example only, either as a singlepill or as two separate pills). One of the therapeutic agents may begiven in multiple doses, or both may be given as multiple doses. If notsimultaneous, the timing between the multiple doses may vary from morethan zero weeks to less than four weeks. In addition, the combinationmethods, compositions and formulations are not to be limited to the useof only two agents; the use of multiple therapeutic combinations arealso envisioned.

It is understood that the dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, can be modifiedin accordance with a variety of factors. These factors include thedisorder or condition from which the subject suffers, as well as theage, weight, sex, diet, and medical condition of the subject. Thus, thedosage regimen actually employed can vary widely and therefore candeviate from the dosage regimens set forth herein.

The pharmaceutical agents which make up the combination therapydisclosed herein may be a combined dosage form or in separate dosageforms intended for substantially simultaneous administration. Thepharmaceutical agents that make up the combination therapy may also beadministered sequentially, with either therapeutic compound beingadministered by a regimen calling for two-step administration. Thetwo-step administration regimen may call for sequential administrationof the active agents or spaced-apart administration of the separateactive agents. The time period between the multiple administration stepsmay range from, a few minutes to several hours, depending upon theproperties of each pharmaceutical agent, such as potency, solubility,bioavailability, plasma half-life and kinetic profile of thepharmaceutical agent. Circadian variation of the target moleculeconcentration may also determine the optimal dose interval.

In addition, the compounds described herein also may be used incombination with procedures that may provide additional or synergisticbenefit to the patient. By way of example only, patients are expected tofind therapeutic and/or prophylactic benefit in the methods describedherein, wherein pharmaceutical composition of a compound disclosedherein and/or combinations with other therapeutics are combined withgenetic testing to determine whether that individual is a carrier of amutant gene that is known to be correlated with certain diseases orconditions.

The compounds described herein and combination therapies can beadministered before, during or after the occurrence of a disease orcondition, and the timing of administering the composition containing acompound can vary. Thus, for example, the compounds can be used as aprophylactic and can be administered continuously to subjects with apropensity to develop conditions or diseases in order to prevent theoccurrence of the disease or condition. The initial administration canbe via any route practical, such as, for example, an intravenousinjection, a bolus injection, infusion over about 5 minutes to about 5hours, a pill, a capsule, transdermal patch, buccal delivery, and thelike, or combination thereof. A compound is preferably administered assoon as is practicable after the onset of a disease or condition isdetected or suspected, and for a length of time necessary for thetreatment of the disease or condition. The length of treatment can varyfor each subject, and the length can be determined using the knowncriteria.

EXAMPLES

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Anhydrous solvents and oven-dried glassware wereused for synthetic transformations sensitive to moisture and/or oxygen.Yields were not optimized. Reaction times are approximate and were notoptimized. Column chromatography and thin layer chromatography (TLC)were performed on silica gel unless otherwise noted. Spectra are givenin ppm (δ) and coupling constants, J are reported in Hertz. For protonspectra the solvent peak was used as the reference peak.

Example 1: Preparation of2-[3-(4-chlorophenyl)ureido]-6-(cyclopropylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamidehydrochloride (9)

Step 1: (5S)-methyl3-hydroxy-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate (2)

To a 3 L round bottom flask equipped with a magnetic stir bar andnitrogen inlet was added (R)-2-Carbomethoxy-3-tropinone 1 (50 g, 254mmol) and methanol (1.01 L). The resulting mixture was stirred rapidlyat room temperature (20±2° C.) under nitrogen for one hour to give abrown clear solution, which was cooled to −72° C. (internal temperature)in a dry ice-acetone bath with continuing stirring under nitrogen.Sodium borohydride (24 g, 635 mmol) was added in one portion and thereaction mixture was first stirred at −72° C. (internal temperature)under nitrogen for 30 minutes, and then moved into another cooling baththat was filled with ethanol and pre-cooled to −20° C. (internaltemperature) with an immersion cooler. The reaction was stirred at −20°C. under nitrogen for 16 hours.

With rapid stirring under nitrogen, the reaction mixture was cooledagain to −72° C. (internal temperature). The nitrogen inlet on thereaction flask was replaced with a Claisen adapter. One joint of theClaisen adapter was connected to the nitrogen inlet. On the other jointof the Claisen adapter was put an addition funnel capped with a septumand containing conc. HCl (115 mL). While stirring rapidly under nitrogenat −72° C., the reaction was quenched by adding conc. HCl dropwise overa period of 45 minutes. After addition was completed, the resultinglight yellow slurry was warmed gradually to room temperature (20±2° C.)over one hour, and then concentrated under reduced pressure (Rotovap at40° C. bath temperature) to give a yellow oily solid. To the 3 L roundbottom flask containing the yellow oily solid residue was added brine(850 mL) in one portion and the resulting light brown solution wascooled to 0-5° C. with an ice-water bath. The 3 L round bottom flask wasequipped again with a Claisen adapter, nitrogen inlet and an additionfunnel containing conc. ammonium hydroxide (140 mL). With ice-water bathcooling and rapid stirring, ammonium hydroxide was dropped into theabove light brown solution to adjust the pH value to about 10 over aperiod of 30 minutes. The aqueous solution was then extracted withmethylene dichloride (950 ml×3), and the combined organic phases weredried over Na₂SO₄. Filtration, concentration (Rotovap at 40° C. bathtemperature) and drying under high vacuum (oil pump) for 16 hours gave alight brown oily solid product 2 (41.5 g, 82%) which is a mixture of3-hydroxytropanes.

Step 2: (5S)-methyl 8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate(3)

To an oven-dried 2 L round bottom flask equipped with a magneticstirring bar and nitrogen inlet was added at room temperature (20±2° C.)compound 2 (41.5 g, 208 mmol) and anhydrous pyridine (414 mL) to form adark red solution, which was then cooled in an ice-water bath withstirring for 30 minutes. To the above stirred solution was dropped inmethanesulfonyl chloride (38.3 mL, 500 mmol) via a scaled additionfunnel over 15 minutes. The resulting mixture was stirred for another 30minutes with ice-water bath cooling. The ice-water bath was then removedand the reaction mixture was stirred at room temperature (20±2° C.)under N₂ for 48 hours. The reaction flask was again cooled in anice-water bath for 25 minutes. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)(156 mL, 1040 mmol) was dropped into the reaction mixture via a scaledaddition funnel over 40 minutes. After addition finished, the stirringwas continued for another 30 minutes. The ice-water bath was thenremoved and the reaction mixture was stirred at room temperature (20±2°C.) under N₂ for 24 hours.

The reaction mixture was carefully added to a 5 L round bottom flaskcharged with a magnetic stirring bar and diethyl ether (2.5 L) over 15minutes with vigorously stirring. After addition finished, stirring wascontinued for another 10 min and then stopped. The mixture was left tostand for 40 min. The dark red ether phase was decanted out and theresidue was washed with ether (350 mL×2). All the ether phases werecombined and concentrated under reduced pressure (first used low vacuumto remove ether, then used high vacuum to remove most of pyridine) atwater bath temperature <45° C. to give dark red oily residue (75 g) thatwas purified using Teledyne ISCO Combiflash automatic chromatographysystem (330 g Redisep silica gel column, Solvent A: 1% Et₃N/10% MeOH/89%EtOAc in Solvent B: 1% Et₃N/99% EtOAc gradient) to give pure product 3(26.3 g, 70%) as a red oil, plus impure product 3 6.6 g; ¹H-NMR (300MHz, CDCl₃) δ 6.82-6.78 (m, 1H, H-3), 3.76 (d, J=5.2 Hz, 1H, H-1), 3.72(s, 3H, OCH₃), 3.22 (t, J=5.5 Hz, 1H, H-5), 2.61 (d, J=19.5 Hz, 1H,H-4_(ax)), 2.33 (s, 3H, NCH₃), 2.21-2.06 (m, 2H), 1.89-1.70 (m, 2H),1.54-1.41 (m, 1H); CIMS [M+1]⁺ 182.

Step 3: (5S)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylic acid (4)

A solution of compound 3 (14.7 g, 81 mmol) in 0.5 N KOH aqueous solution(324 mL, 162 mmol) in a 1 L round bottom flask was heated to reflux (oilbath 135-140° C.) for 40 min. The clear yellow solution was cooled downto room temperature (20±2° C.), then put into an ice-water bath andacidified with 1 N HCl (˜160 ml) to pH=6. Concentration under reducedpressure gave a yellow solid, which was extracted with absolute ethanol(400 ml×3). Combined extracts were filtered and concentrated underreduced pressure to give 4 (13 g, 96%) as a light yellow solid; ¹H-NMR(300 MHz, DMSO-d6) δ 6.58-6.52 (m, 1H, H-3), 3.59 (d, J=5.2 Hz, 1H,H-1), 3.12 (t, J=5.2 Hz, 1H, H-5), 2.52-2.41 (m, 1H, H-4_(ax)), 2.20 (s,3H, NCH₃), 2.05-1.88 (m, 2H), 1.76 (dd, J=19.5, 4.4 Hz, 1H, H-4_(eq)),1.66-1.58 (m, 1H), 1.46-1.36 (m, 1H); CIMS [M+1]⁺ 168.

Step 4: (5S)-8-methyl-8-azabicyclo[3.2.1]octan-2-one (5)

To an oven-dried 2 L round bottom flask equipped with a magnetic stirbar and nitrogen inlet was added compound 4 (13 g, 77.8 mmol), Na₂CO₃(11.6 g, 109 mmol) and DMAP (238 mg, 1.9 mmol). Under nitrogenatmosphere, anhydrous methylene dichloride (292 mL) was added to theabove flask followed by the addition of diphenyl phosphoryl azide (DPPA)(20.2 mL, 93.4 mmol). The resulted reaction mixture was stirredvigorously at room temperature (20±2° C.) for 65 hours to form anoff-white to light yellow slurry. Volatile components were removed underreduced pressure and the residue was dissolved in water (78 mL) followedby the slowly and carefully addition of 1N HCl (340 mL). The mixture washeated to reflux (oil bath 120° C.) for 50 minutes until gas evolutionceased. After concentration under reduced pressure, the residue wasbrought to basic (pH≈10) with saturated aqueous Na₂CO₃ solution andextracted with methylene dichloride (500 mL×2) and chloroform (500mL×2). The combined organic phases were dried over Na₂SO₄. Filtrationand concentration gave yellow liquid residue (14.95 g), which waspurified using Teledyne ISCO Combiflash automatic chromatography system(220 g Redisep silica gel column, first eluent with EtOAc in CH₂Cl₂gradient, then with 1% Et₃N/99% EtOAc in CH₂Cl₂) to give pure product 5(6.5 g, 60%) as a slightly yellow oil; ¹H-NMR (300 MHz, CDCl₃) δ3.34-3.28 (m, 1H, H-5), 3.27 (d, J=6.9 Hz, 1H, H-1), 2.40 (s, 3H, NCH₃),2.39-2.15 (m, 5H), 1.81-1.66 (m, 3H).

Step 5:(4R,7S)-2-amino-9-methyl-5,6,7,8-tetrahydro-4H-4,7-epiminocyclohepta-[b]thiophene-3-carbonitrile(6)

To a mixture of compound 5 (6.5 g, 46.7 mmol), malononitrile (3.39 g,51.4 mmol) and sulfur (1.64 g, 51.4 mmol) in absolute ethanol (75 mL) inan oven-dried 250 ml round bottom flask at room temperature (20±2° C.)under nitrogen atmosphere was dropped in morpholine (11 mL, 131 mmol) in5 minutes. After addition was completed, the reaction mixture was heatedat 50° C. under nitrogen atmosphere with stirring for 16 hours to give adark black brown solution. Upon cooling to room temperature (20±2° C.),the reaction mixture was mixed with 25 g of silica gel, concentrated todryness and purified using Teledyne ISCO Combiflash automaticchromatography system (120 g Redisep silica gel column, eluent withEtOAc in CH₂Cl₂ gradient) to give 6 (9.01 g, 88%) as a light brownsolid; ¹H-NMR (300 MHz, DMSO-d6) δ 7.02 (s, br, 2H, —NH₂), 3.53 (d,J=5.2 Hz, 1H, H-1), 3.36-3.29 (m, 1H, H-5), 2.78 (dd, J=16.2, 4.4 Hz,1H, H-4_(ax)), 2.21 (s, 3H, NCH₃), 2.15-1.95 (m, 3H), 1.70-1.61 (m, 1H),1.50-1.41 (m, 1H); CIMS [M+1]⁺ 220.

Step 6:(4R,7S)-2-amino-9-methyl-5,6,7,8-tetrahydro-4H-4,7-epiminocyclohepta-[b]thiophene-3-carboxamide(7)

A 250 ml round bottom flask charged with 6 (9.01 g, 41 mmol) and amagnetic stir bar was cooled in an ice-water bath. Conc. sulfuric acid(41 mL) precooled in an ice-water bath was dropped in slowly withstirring to form a dark black brown solution. The reaction solution wasstirred at room temperature (20±2° C.) for 40 hours and then cooled inan ice-water bath and slowly added into an ice-water cooled 10% NaOHaqueous solution (450 mL). The resulted aqueous solution was adjusted topH=10 with 10% NaOH aqueous solution and extracted with methylenedichloride (contain 5-10% methanol, 650 mL×2) and chloroform (contain5-10% methanol, 650 mL×2). The combined organic extracts were dried overNa₂SO₄. Filtration and concentration gave 7 (9.36 g, 96%) as a brownsolid; ¹H-NMR (300 MHz, DMSO-d6) δ 6.70 (s, br, 2H, —NH₂), 6.50 (s, br,2H, —CONH₂), 4.01 (d, J=5.0 Hz, 1H, H-1), 3.35-3.25 (m, 1H, H-5), 2.84(dd, J=16.2, 4.4 Hz, 1H, H-4_(ax)), 2.20 (s, 3H, NCH₃), 2.09-1.97 (m,3H), 1.79-1.69 (m, 1H), 1.50-1.39 (m, 1H); CIMS [M+1]⁺ 238.

Step 5/6:(4R,7S)-2-amino-9-methyl-5,6,7,8-tetrahydro-4H-4,7-epiminocyclohepta-[b]thiophene-3-carboxamide(7)

In an alternate procedure, the chemical transformations in Steps 5 and 6were carried out in a single step. To a mixture of (1R)-2-tropinone(32.0 g, 0.23 mol), 2-cyanoacetamide (21.6 g, 0.25 mol) and sulfur (8.2g, 0.26 mol) in absolute ethanol (370 mL) in an oven-dried 1000 mL3-necked roundbottom flask at room temperature (15±2° C.) under nitrogenatmosphere was dropped in morpholine (57.0 g, 0.66 mol) in 20 minutes.After addition was completed, the reaction mixture was heated at 50° C.under nitrogen atmosphere with stirring for 30 hours to give a solution.The reaction was repeated once. Upon cooling to room temperature (15±2°C.), the two batches of reaction mixture was mixed with 180 g of silicagel, concentrated to dryness and purified using Combiflash automaticchromatography system (900 g silica gel column, eluent with MeOH inCH₂Cl₂ gradient, 0-10%). The product was slurried with 210 mL of MTBEand collected to afford 7 (89 g, 82%) as a light yellow solid.

Step 7:(4R,7S)-2-(3-(4-chlorophenyl)ureido)-9-methyl-5,6,7,8-tetrahydro-4H-4,7-epiminocyclohepta[b]thiophene-3-carboxamide(8)

To a mixture of 7 (9.36 g, 39.5 mmol) and anhydrous methylene chloride(360 mL) in a 2 L round bottom flask at room temperature (20±2° C.)under nitrogen atmosphere was dropped in through an addition funnel asolution of 4-chlorophenyl isocyanate (6.67 g, 43.5 mmol) in anhydrousmethylene chloride (250 mL) over 20 minutes. After addition wascompleted, the reaction mixture was stirred under nitrogen atmosphere atroom temperature (20±2° C.) for 16 hours. The reaction mixture was mixedwith 100 mL methanol and 25 g of silica gel, concentrated to dryness andpurified using Teledyne ISCO Combiflash automatic chromatography system(330 g Redisep silica gel column, first eluent with EtOAc in CH₂Cl₂gradient, then with 1% Et₃N/10% MeOH/89% EtOAc in CH₂Cl₂ gradient) toafford 15.8 g light brown solid product that was recrystallized frommethanol/hexane to give 8 (10.1 g, 65%) as a slightly yellow tooff-white solid: mp 154-156° C.; [α]²² _(D)=+19.05 (c=0.2, MeOH); ¹H-NMR(300 MHz, DMSO-d6) δ 10.70 (s, br, 1H, NH—CO), 10.05 (s, br, 1H, NH—CO),7.51 (d, J=8.8 Hz, 2H, ArH), 7.31 (d, J=8.8 Hz, 2H, ArH), 7.10 (s, br,2H, —CONH₂), 4.21-4.05 (m, br, 1H, H-1), 3.49-3.30 (m, br, 1H, H-5),2.99 (d, J=15.3 Hz, 1H, H-4_(ax)), 2.39-1.98 (m, 6H), 1.91-1.70 (m, br,1H), 1.48 (s, br, 1H); CIMS [M+1]⁺ 391; Analytical HPLC column: AgilentZorbax SB-C18, 5 μm, 4.6×150 mm, mobile phase A: acetonitrile with 0.1%trifluoroacetic acid, mobile phase B: water with 0.1% trifluoroaceticacid, use gradient: A in B 5% to 95% in 9 min, flow rate: 1 ml/min,column temperature: 20±2° C., detector: λ=254 nm, t_(R)=4.2 min; ChiralHPLC column: Chiralcel OD, mobile phase A: 1% diethylamine in hexane,mobile phase B: 1% diethylamine in ethanol, A:B=1:1 (v/v), flow rate:0.76 ml/min, column temperature: 20±2° C., detector: λ=254 nm,t_(R)=15.3 min >99%.

Step 8:(4R,7S)-2-(3-(4-chlorophenyl)ureido)-9-methyl-5,6,7,8-tetrahydro-4H-4,7-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride (9)

A solution of 8 (16.8 g, 43 mmol) in methanol (1.5 L) in a 3 L roundbottom flask was cooled in an ice-water bath. White precipitatesappeared. While stirring, 1 N HCl (64 mL) was dropped in over 5 minutesand the system gradually turned into a clear solution. After additionwas completed, the solution was stirred at room temperature (20±2° C.)for 15 minutes and diluted with water (450 mL). All the methanol wasevaporated under reduced pressure and the residue was mixed with water(450 mL) and lyophilized to give the title compound (9) (18.0 g) as anoff-white solid: mp 200-202° C.; [α]²² _(D)=+4.65 (c=0.2, MeOH); ¹H-NMR(300 MHz, DMSO-d6) δ 11.22 (s, br, 0.31H, —NH), 10.33 (s, 0.63H, NH—CO),10.31 (s, 0.37H, NH—CO), 10.18 (s, 0.63H, NH—CO), 10.17 (s, br, 0.61H,—NH), 10.15 (s, 0.37H, NH—CO), 7.49 (dd, J=9.0, 2.2 Hz, 2H, ArH), 7.45(s, br, 2H,—CONH₂), 7.35 (dd, J=9.0, 2.2 Hz, 2H, ArH), 4.93-4.87 (m, br,1H, H-1), 4.21-4.15 (m, br, 0.63H, H-5), 4.15-4.05 (m, br, 0.37H, H-5),3.38 (dd, J=16.5, 4.1 Hz, 0.61H, H-4_(ax)), 3.20 (dd, J=18.4, 4.9 Hz,0.39H, H-4_(ax)), 2.89-2.76 (m, 1H, H-4 eq), 2.80 (d, J=4.9 Hz, 2H,NCH₃), 2.69 (d, J=4.9 Hz, 1H, NCH₃), 2.49-2.22 (m, 2H), 2.21-2.06 (m,1H), 1.92-1.76 (m, 1H); ¹³C-NMR (75 MHz, DMSO-d6) δ 166.3 (0.4C), 166.2(0.6C), 151.9, 145.6 (0.4C), 145.5 (0.6C), 138.8, 132.0 (0.6C), 129.3(2C), 128.0 (0.4C), 126.5, 120.8, 120.3 (2C), 114.1 (0.4C), 113.3(0.6C), 62.5 (0.6C), 62.1 (0.6C), 60.2 (0.4C), 58.2 (0.4C), 33.8 (0.4C),32.6 (0.6C), 32.4 (0.6C), 31.2 (0.4C), 28.1 (0.6C), 27.6 (0.6C), 25.8(0.8C); CIMS [M+1]⁺ 391; Analytical HPLC column: Agilent Zorbax SB-C18,5 m, 4.6×150 mm, mobile phase A: acetonitrile with 0.1% trifluoroaceticacid, mobile phase B: water with 0.1% trifluoroacetic acid, usegradient: A in B 5% to 95% in 9 min, flow rate: 1 ml/min, columntemperature: 20±2° C., detector: λ=254 nm, t_(R)=4.2 min; Chiral HPLCcolumn: Chiralcel OD, mobile phase A: 1% diethylamine in hexane, mobilephase B: 1% diethylamine in ethanol, A:B=1:1 (v/v), flow rate: 0.76ml/min, column temperature: 20±2° C., detector: λ=254 nm, t_(R)=15.3min >99%; Anal. Calcd for C₁₈H₂₀Cl₂N₄O₂S.2H₂O: C, 46.66; H, 5.22; N,12.09; Found C, 46.67; H, 5.15; N, 12.14.

The N-methyl group of compound 9 exists in both a pseudo equatorial andpseudo axial orientation. This gives rise to duplicate ¹H-NMR resonancesfor the methyl group as well as other affected protons. These effectsare also observed in the ¹³C-NMR spectrum. The H and C resonances aretherefore reported as fractional values.

Example 2: Preparation of(4R,7S)-2-(3-(4-chlorophenyl)ureido)-5,6,7,8-tetrahydro-4H-4,7-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride (10)

The title compound (10) is prepared in a similar manner as described inExample 1.

Example 3: Preparation of(4R,7S)-2-[3-(4-chlorophenyl)ureido]-5,8-dimethyl-5,6,7,8-tetrahydro-4H-4,7-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride (11)

The title compound (11) is prepared in a similar manner as described inExample 1.

Example 4: Preparation of(4R,7S)-2-[3-(4-benzoylphenyl)ureido]-9-methyl-5,6,7,8-tetrahydro-4H-4,7-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride (12)

The title compound (12) is prepared in a similar manner as described inExample 1.

Example 5: Preparation of(4R,7S)-2-[3-(4-chlorophenyl)ureido]-9-(cyclohexylmethyl)-5,6,7,8-tetrahydro-4H-4,7-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride (13)

The title compound (13) is prepared in a similar manner as described inExample 1.

Example 6: Preparation of(4R,7S)-2-[3-(4-chlorophenyl)ureido]-9-(cyclobutylmethyl)-5,6,7,8-tetrahydro-4H-4,7-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride (14)

The title compound (14) is prepared in a similar manner as described inExample 1.

Example 7: Preparation of(4R,7S)-2-[3-(4-chlorophenyl)ureido]-9-ethyl-5,6,7,8-tetrahydro-4H-4,7-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride (15)

The title compound (15) is prepared in a similar manner as described inExample 1.

Example 8: Preparation of (4R,7S)-Methyl3-{3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-5,6,7,8-tetrahydro-4H-4,7-epiminocyclohepta[b]thiophen-9-yl}-2,2-dimethylpropanoatehydrochloride (16)

The title compound (16) is prepared in a similar manner as described inExample 1.

Example 9: Preparation of(4R,7S)-3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-9,9-dimethyl-5,6,7,8-tetrahydro-4H-thienocyclohepten-4,7-iminiumiodide (17)

A solution of compound 8 and iodomethane (1.3 equivalents) inN,N-dimethylformamide is stirred at room temperature for 18 h. Thereaction mixture is then concentrated under reduced pressure. Theresulting residue is triturated with methylene chloride to give compound17.

Example 10: Preparation of(4R,7S)-3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-9-ethyl-9-methyl-5,6,7,8-tetrahydro-4H-thienocyclohepten-4,7-iminiumiodide (18)

The title compound (18) is prepared in a similar manner as described inExample 9.

Example 11: Preparation of(4R,7S)-3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-9-(cyclobutylmethyl)-9-methyl-5,6,7,8-tetrahydro-4H-thienocyclohepten-4,7-iminiumiodide (19)

The title compound (19) is prepared in a similar manner as described inExample 9.

Biological Assays Example 12: Neomycin Hair Cell Toxicity Assay inZebrafish

Zebrafish are bred and newly fertilized embryos are collected the weekprior and raised at 28.5° C. in petri dishes containing embryo medium.Newly hatched free-swimming larvae are fed paramecium and dry fish foodat 4 days post fertilization (dpf) with lights on. For treatment, fish5-7 dpf are transferred to cell culture baskets and place within a wellof a 6-well plate containing 7 milliliters of 1× embryo medium.Typically, tests are done with ten fish per basket but work well with upto 50 fish. All treatment and wash volumes are 7 milliliters.

1. Fish are pre-treated with test compound for 1 hour. Concentrationsbetween 0.010 to 25 micromolar of test compound are tested.2. Treat with 200 micromolar neomycin (neomycin sulfate, Sigma, St.Louis, Mo., catalog #N1142)+ test compound for 30 minutes.3. Rinse fish briefly 4 times in embryo medium and add 700 μl of 0.05%DASPEI (2-{4-(dimethylamino)styryl}-N-ethylpyridinium iodide, MolecularProbes, Eugene, Oreg.) and allowed to stain for 15 minutes.4. Rinse twice in embryo medium and add 350 μL MS222 (0.55 ug/ml finalconcentration, 3-aminobenzoic acid ethyl ester, methansulfoneate salt,Sigma, St. Louis, Mo.) to anesthetize.5. View with epifluorescence dissecting microscope equipped with aDASPEI filter set (excitation 450-490 nM and barrier 515 nM, ChromaTechnologies, Brattleboro, Vt.). For assessment of initial dose responsecurves, fish are transferred to wide depression slide with wide-borepipette. The DASPEI staining of ten neuromasts (SO1, SO2, IO1, IO2, IO3,IO4, M2, MI1, MI2 and O2) on one side of an animal are evaluated. Eachneuromast is scored for presence of DASPEI staining (score=2), reducedDASPEI staining (score=1) or absence of DASPEI staining (score=0). Totalscores for an animal are tabulated, to give a composite score that canrange from 0 to 20. Average scores and standard deviations arecalculated for animals in each treatment group. Scores are normalized tocontrol group (vehicle only, no drug, no neomycin) and expressed as %hair cell survival. HCmax is the maximum protection (hair cell survival)observed. 6. If at least 50% hair cells survive, the HC50 (concentrationthat would produce 50% hair cell survival) is calculated as a linearextrapolation from the nearest concentrations of protective drug thatproduce hair cell survival below and above 50%. If less than 50% haircells survive, the HC50 is not determined.1× embryo media (standard lab EM):

1 mM MgSO₄,

0.15 mM KH₂PO₄,0.05 mM Na₂HPO₄,

1 mM CaCl₂, 0.5 mM KCl 15 mM NaCl 0.7 mM NaHCO₃

The results for compound 9 in the Neomycin Hair Cell Toxicity Assay areshown in Table 1.

TABLE 1 Compound HC₅₀ Max HC Protection 9 <1.0 μM 96% protection at 2.6μM

Example 13: Cisplatin Hair Cell Toxicity Assay in Zebrafish

Zebrafish are bred and newly fertilized embryos are collected the weekprior and raised at 28.5° C. in petri dishes containing embryo medium.Newly hatched free-swimming larvae are fed paramecium and dry fish foodat 4 days post fertilization (dpf) with lights on. For treatment, fish5-7 dpf are transferred to cell culture baskets and place within a wellof a 6-well plate containing 7 milliliters of 1× embryo medium.Typically, tests are done with ten fish per basket but work well with upto 50 fish. All treatment and wash volumes are 7 milliliters.

-   -   1. In a 48-well plate, place 10-12 fish/well in 300 μl of EM.    -   2. Add ORC-13661 and vehicle control to each well at        concentrations listed below. Swirl and place in incubator for 15        min. ORC-13661 concentrations tested: 0.103 μM, 0.308 μM, 0.925        μM, 2.78 μM, 8.33 μM.    -   3. Add cisplatin 50 μM to pretreated and control wells. Swirl        and place in incubator for 24 hrs.    -   4. Place 1-2 drops of MS222 in each well to anesthetize fish,        then aspirate treated EM.    -   5. Add 300 μl/well of 4% paraformaldehyde to fix fish. Fix        overnight at 4° C. or 2 hrs at room temperature (RT).    -   6. Rinse wells with PBS for 15 min each 3 times.    -   7. Add 300 μl/well of blocking solution for 1 hr at RT.    -   8. Incubate with 300 μl/well of 1:400 mouse anti-Parvalbumin        antibody overnight at 4° C.    -   9. Rinse wells with PBS-T for 15 min each 3 times.    -   10. Incubate with 300 μl/well of 1:500 Alexa 488 goat anti-mouse        secondary antibody for 2-4 hrs at RT.    -   11. Rinse wells with PBS-T for 15 min each 3 times.    -   12. Rinse wells with PBS for 15 min each 3 times.    -   13. Mount each group of fish on coverslips with Fluoromount G.        Image on Zeiss Axioplan at 40× magnification with GFP filter and        count number of hair cells in 4 neuromasts: SO1, SO2, O1, OC1.    -   14. Average the total number of hair cells from the 4 neuromasts        per fish in each treatment group and normalize to vehicle        control group to get hair cell counts as % control+/− standard        deviation.

The results for compound 9 in the Cisplatin Hair Cell Toxicity Assay areshown in Table 2 and FIG. 1.

TABLE 2 Compound HC₅₀ Max HC Protection 9 <1.0 μM 90% protection at 8.33μM

Example 14: Auditory Brainstem Response (ABR) Assay

Chronic treatment of rats with aminoglycosides (AGs) such as kanamycinor amikacin results in an elevation of ABR thresholds, typically mostpronounced at higher frequencies. For rats, hearing is tested at a rangeof frequencies to determine the intensity of sound (measured indecibels) necessary to evoke a response. As hearing loss becomes moresevere, a higher intensity is needed to evoke a response. Each ratserves as its own control; hearing thresholds are determined at eachfrequency prior to any treatment and then at 2 weeks after a 10-daycourse of AG treatment (or control drug exposures).

The ABR assay measures short latency field potentials recorded from thescalp of animals that were sedated or noninvasively immobilized. Aseries of 10-1000 clicks or pure tone pulses were presented to theanimal at a rapid rate, resulting in a stereotyped series of waveformsreflecting the electrical events in brain stem auditory regions. Foreach animal, hearing thresholds, wave 1 latencies and input-outputfunctions for stimulus frequencies at 2, 4, 8, 16 and 32 kHz weremeasured prior to any treatment to determine the initial sensitivity anddynamic range of hearing, and then repeated at the end of drug treatmentand at the end of the experiment (2-weeks after dosing).

Treatment Groups:

-   -   Amikacin (SC) @ 320 mg/kg/day for 10 days; n=13 (hereafter        “AMI/320”)    -   AMI/320+ Compound 9 (PO) @ 5 mg/kg/day for 10 days n=7    -   Compound 9 alone @ 5 mg/kg/day for 10 days; n=5    -   Vehicle of Compound 9 (IP) for 10 days; n=6.

ABR records were evaluated by a “blinded”, trained experimenter. Hearingloss (Threshold Shift) was determined by subtracting the thresholdduring pre-treatment (Day 0) from the final ABR threshold (Day 24; twoweeks following treatment). Within the variation of the test, a positivevalue means that the rat suffered hearing loss during the exposureperiod. This was seen in the animals treated with amikacin alone (FIG.2). Co-administration of Compound 9 led to robust protection of the highfrequency loss due to Amikacin exposure (FIG. 2). Animals in the controlgroups showed no significant change in threshold at any frequency overthe study period (FIG. 2).

Example 15: Effect of Amikacin and Compound 9 on Kidney Function

The study consisted of three groups of Fischer 344 rats aged 6 weeks andweighing approximately 200 g at the start of the study. Group 1consisted of six rats, randomly selected to receive amikacin only, Group2 consisted of six rats chosen randomly to receive amikacin and compound9, and Group 3 consisted of three rats, 2 rats given compound 9 and 1rat given only 0.5% Methylcellulose, the diluent for compound 9. Allanimals receiving amikacin were given 320 mg/kg subcutaneously (SQ) froma freshly prepared solution of amikacin of 40 mg/mL. The compound 9formualtion was prepared by weighing 13.08 mg of compound 9 dissolved in12 mL of 0.5% MC in saline with vortexing, sonification andhomogenization to obtain a solution with concentration at 12 mg/12 mL=1mg/mL, dose volume is 5 mL/kg (5 mg/kg). The compound 9 solution wasgiven by oral gavage at a dose of 5 mg/kg.

One day prior to the onset of dosing, blood was drawn from all rats forserum analysis and all rats were put into metabolic cages for 24 hoururine collection and analysis. All rats were returned to normal cagesand allowed to eat and drink ad lib. All rats received their assignedtreatments for 10 days and then were returned to metabolic cages for the10^(th) day. Three rats were randomly chosen from each of Group 1 andGroup 2 to have additional blood draws at 30 min, 60 mn, 2 hr, 4 hr, 8hr and 24 hr after the 10^(th) dose for amikacin and compound 9 PKanalysis. All rats had blood drawn for serum analysis at the end of day10 and the 24 hour urine collected from day 10. After the final blooddraw, all rats were euthanized and their kidneys removed and preparedfor histopathology testing. The left kidneys were longitudinallysectioned, the right kidneys were cross sectioned. The pathologist readthe slides, blinded to the group from which they were assigned. Theygraded viewed five different locations on each slide and gave eachlocation a score for degree of damage: no damage (0 score); minimal(1-10%, 1 score), mild (11-20%, 2 score), moderate (21-50%, 3 score), ormarked (51-100%, 4 score).

Previous studies have shown that aminoglycoside renal toxicity primarilyaffects the proximal and distal tubules of the kidney, eventuallycausing apotheosis of the epithelial cells. The resulting damage causes,in part, decreased glomerular filtration rate (GFR) which may be aresult of the tubular damage or partly through other mechanisms. The GFRwas approximated using the creatinine clearance. The first objective ofthis experiment was to demonstrate that amikacin given at 320 mg/kg/dayfor 10 days was sufficient to cause significant nephrotoxicity measuredby a reduction in creatinene clearance; and second that rats treatedwith amikacin plus compound 9 have significantly less renal toxicitymeasured by an increase in creatinine clearance relative to amikacinonly rats. FIG. 3 shows the the mean and standard error of the mean ofthe creatinine clearance (CrCl) in rats from Group 1 and 2post-treatment compared to their pretreatment values. The one-sidedtwo-sample t-test p-value for the comparison of the amikacin only(Group 1) and amikacin+compound 9 (Group 2) are shown in a box betweenthe two columns. Both Group 1 and Group 2 animals post treatment aresignificantly different from baseline and these significance levels arenot shown.

FIG. 4 shows the results of the histopathology of amikacin only ratsversus that of the amikacin+compound 9 treated rats for each thelongitudinal sectioning of the kidney and the cross sectioning of thekidney. Although the differences are not great numerically, they aresignificant at p<0.005 level. A 4 means close to 100% damage, while a 3means <50% damage, so a change of 3.9 to 3.6 is meaningful and a changeof 3.9 to 3.1 may mean an improvement of as much as 50% in the damagecaused.

Example 16: Clinical Trial of the Protective Effect of a Compound ofFormula (I), (Ia), (Ib), (II), (IIa), or (IIb) Against Ototoxicity

The majority of patients with Cystic Fibrosis that live to adulthoodhave periodic bouts of pulmonary pseudomonas infections severe enough towarrant parenteral aminoglycoside therapy despite their potential riskfor ototoxicity. At least 20% of adult cystic fibrosis patients havedefinite measurable hearing loss, especially in the higher frequenciesas measured by standard and high frequency audiometric tests. Renaltoxicity is another frequent unwanted side effect occurring in as manyas 7% of the patients treated with aminoglycosides. The purpose of thisstudy is to examine whether ototoxicity and renal toxicity due toparenteral aminoglycosides therapy for pseudomonas infections inpatients with cystic fibrosis can be prevented by a compound of Formula(I), (Ia), (Ib), (II), (IIa), or (IIb).

Patients: Eligible subjects will be men and women 18-65 years of age.

Inclusion Criteria

-   -   Definitive diagnosis of Cystic Fibrosis    -   Scheduled for hospital or ambulatory intravenous treatment of        pulmonary pseudomonas infections using only an aminoglycoside        antibiotic    -   Has normal or near normal renal function

Exclusion Criteria

-   -   Has been treated with parenteral aminoglycoside antibiotics        within the previous 3 months    -   Detection of mechanical occlusion of external ear    -   Having signs of disturbed integrity of tympanic membrane on        otoscopy or tympanometry    -   Has >20 db hearing loss at all frequencies below 8 khtz

Study Design:

Arms Experimental: Compound of Formula (I), (Ia), (Ib), (II), (IIa), or(IIb) Compound of Formula (I), (Ia), (Ib), (II), (IIa), or (IIb) 5 mg/kgpo daily + amikacin or tobramycin Tobramycin or amikacin alone

Primary Outcome Measures

-   -   Compare threshold hearing levels change from before therapy to 4        weeks following the completion of therapy between the two arms        using standard and high frequency audiometric tests.    -   Compare changes in creatinine clearance, urine Kim-1, serum        creatinine and Bun from before therapy to the day following the        completion of therapy between the two arms.

What is claimed is:
 1. A compound having the structure of Formula (I):

wherein: Z is a single bond, double bond, —CH₂—, or —O—; R₁ is aryl orheteroaryl, wherein aryl and heteroaryl are optionally substituted withone or more R₄; R₂ is H, C₁-C₆alkyl, C₁-C₆alkyl-OR₆,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₂-C₇heterocycloalkyl,C₁-C₆alkyl-CO₂R₆, optionally substituted C₁-C₆alkylaryl, or optionallysubstituted C₁-C₆alkylheteroaryl; R₃ and R₅ are each independently H, orC₁-C₆alkyl; or R₃ and R₅ together form an optionally substitutedC₃-C₆cycloalkyl ring, optionally substituted C₂-C₇heterocycloalkyl ring,optionally substituted aryl ring, or an optionally substitutedheteroaryl ring; each R₄ is independently selected from F, Cl, Br, I,—CN, —NO₂, —CF₃, —OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉,—N(R₈)C(O)R₁₀, —N(R₈)CO₂R₁₀, —NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl,C₃-C₆cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,C₂-C₇heterocycloalkyl, aryl, and heteroaryl; R₆ is H, or C₁-C₆alkyl; R₈is H, or C₁-C₆alkyl; R₉ is H, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylaryl, orC₁-C₆alkylheteroaryl; R₁₀ is C₁-C₆alkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylaryl, orC₁-C₆alkylheteroaryl; R₁₁ is H, C₁-C₆alkyl, C₁-C₆haloalkyl,C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl, heteroaryl,C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylaryl, or C₁-C₆alkylheteroaryl; R₁₂is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl,C₂-C₇heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkylC₃-C₆cycloalkyl,C₁-C₆alkylaryl, or C₁-C₆alkylheteroaryl; or R₁₁ and R₁₂ together withthe nitrogen to which they are attached form an optionally substitutedC₂-C₇heterocycloalkyl ring; and R₁₃ and R₁₄ are each independently H, orC₁-C₆alkyl; or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate or hydrate, pharmaceutically acceptable salt hydrate,or pharmaceutically acceptable prodrug thereof.
 2. The compound of claim1 or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof, having the structure ofFormula (Ia):


3. The compound of claim 1 or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,having the structure of Formula (Ib):


4. The compound of any one of claims 1-3 wherein R₁ is aryl optionallysubstituted with one or more R₄.
 5. The compound of claim 4 wherein R₁is phenyl optionally substituted with one or more R₄.
 6. The compound ofclaim 5 wherein R₁ is phenyl substituted with one or more R₄, whereineach R₄ is independently selected from F, C, Br, I, —CN, —NO₂, —CF₃,—OR₉, —OCF₃, —NR₈R₉, —C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl.7. The compound of claim 6 wherein R₁ is phenyl substituted with one R₄,wherein R₄ is selected from F, C, Br, I, —CN, —CF₃, —OR₉, —OCF₃,—C(O)R₁₀, —CO₂R₉, and C₁-C₆alkyl.
 8. The compound of claim 7 wherein R₁is 4-chlorophenyl.
 9. The compound of any one of claims 1-8 wherein R₁₁and R₁₂ are each H.
 10. The compound of any one of claims 1-9 wherein R₂is H.
 11. The compound of any one of claims 1-9 wherein R₂ isC₁-C₆alkyl.
 12. The compound of claim 11 wherein R₂ is —CH₃.
 13. Thecompound of any one of claims 1-12 wherein R₁₃ and R₁₄ are each H. 14.The compound of any one of claims 1-12 wherein R₁₃ and R₁₄ are each—CH₃.
 15. The compound of any one of claims 1-14 wherein R₃ and R₅ areeach H.
 16. The compound of any one of claims 1-15 wherein Z is a singlebond.
 17. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.
 18. The compound of claim 1having the structure:

or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.
 19. The compound of claim 1having the structure:

or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate or hydrate, pharmaceutically acceptable salt hydrate, orpharmaceutically acceptable prodrug thereof.
 20. A compound having thestructure of Formula (II):

wherein: X⁻ is a counterion; Z is a single bond, double bond, —CH₂—, or—O—; R₁ is aryl or heteroaryl, wherein aryl and heteroaryl areoptionally substituted with one or more R₄; R_(2a) is C₁-C₆alkyl,—C₁-C₆alkyl-OR₅, or —C₁-C₆alkylC₃-C₆cycloalkyl; R₂ is C₁-C₆alkyl,—C₁-C₆alkyl-OR₆, —C₁-C₆alkylC₃-C₆cycloalkyl, or —C₁-C₆alkyl-CO₂R₆; R₃and R₅ are each independently H, or C₁-C₆alkyl; or R₃ and R₅ togetherform an optionally substituted C₃-C₆cycloalkyl ring, optionallysubstituted C₂-C₇heterocycloalkyl ring, optionally substituted arylring, or an optionally substituted heteroaryl ring; each R₄ isindependently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃, —OR₉, —OCF₃,—NR₈R₉, —C(O)R₁₀, —CO₂R₉, —C(O)NR₈R₉, —N(R₈)C(O)R₁₀, —N(R₈)CO₂R₁₀,—NHS(O)₂R₁₀, —S(O)₂NR₈R₉, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₁-C₆heteroalkyl,C₁-C₆haloalkyl, C₂-C₇heterocycloalkyl, aryl, and heteroaryl; R₆ is H, orC₁-C₆alkyl; R₈ is H, or C₁-C₆alkyl; R₉ is H, C₁-C₆alkyl,C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl, heteroaryl,—C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl; R₁₀ is C₁-C₆alkyl,C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl, heteroaryl,—C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl; R₁₁ is H, C₁-C₆alkyl,C₁-C₆haloalkyl, C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl,heteroaryl, —C₁-C₆alkylC₃-C₆cycloalkyl, —C₁-C₆alkylaryl, or—C₁-C₆alkylheteroaryl; R₁₂ is H, C₁-C₆alkyl, C₁-C₆haloalkyl,C₃-C₆cycloalkyl, C₂-C₇heterocycloalkyl, aryl, heteroaryl,—C₁-C₆alkylC₃-C₆cycloalkyl, —C₁-C₆alkylaryl, or —C₁-C₆alkylheteroaryl;or R₁₁ and R₁₂ together with the nitrogen to which they are attachedform an optionally substituted C₂-C₇heterocycloalkyl ring; and R₁₃ andR₁₄ are each independently H, or C₁-C₆alkyl; or a pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate or hydrate,pharmaceutically acceptable salt hydrate, or pharmaceutically acceptableprodrug thereof.
 21. The compound of claim 20 or a pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate or hydrate,pharmaceutically acceptable salt hydrate, or pharmaceutically acceptableprodrug thereof, having the structure of Formula (IIa).


22. The compound of claim 20 or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,having the structure of Formula (IIb).


23. The compound of any one of claims 20-22 wherein R₁ is aryl.
 24. Thecompound of claim 23 wherein R₁ is phenyl.
 25. The compound of claim 24wherein R₁ is substituted with one or more R₄, wherein each R₄ isindependently selected from F, Cl, Br, I, —CN, —NO₂, —CF₃, —OR₉, —OCF₃,—NR₈R₉, —C(O)R₁₀, —CO₂R₉, C₁-C₆alkyl, and C₁-C₆haloalkyl.
 26. Thecompound of claim 25 wherein R₁ is substituted with one R₄, wherein R₄is selected from F, Cl, Br, I, —CN, —CF₃, —OR₉, —OCF₃, —C(O)R₁₀, —CO₂R₉,and C₁-C₆alkyl.
 27. The compound of claim 26 wherein R₁ is4-chlorophenyl.
 28. The compound of any one of claims 20-27 wherein R₁₁and R₁₂ are each H.
 29. The compound of any one of claims 20-28 whereinR₂ is —C₁-C₆alkyl.
 30. The compound of any one of claims 20-29 whereinR_(2a) is C₁-C₆alkyl.
 31. The compound of any one of claims 20-30wherein R₁₃ and R₁₄ are each H.
 32. The compound of any one of claims20-30 wherein R₁₃ and R₁₄ are each CH₃.
 33. The compound of any one ofclaims 20-32 wherein R₃ and R₅ are each H.
 34. The compound of any oneof claims 20-33 wherein Z is a single bond.
 35. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof any one of claims 1-34, or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,and a pharmaceutically acceptable excipient, and a pharmaceuticallyacceptable excipient.
 36. The pharmaceutical composition of claim 35further comprising an aminoglycoside antibiotic.
 37. The pharmaceuticalcomposition of claim 36 wherein the aminoglycoside antibiotic isselected from streptomycin, neomycin, framycetin, paromomycin,paromomycin sulfate, ribostamycin, kanamycin, amikacin, arbekacin,bekanamycin, dibekacin, tobramycin, spectinomycin, hygromycin B,gentamicin, netilmicin, sisomicin, isepamicin, verdamicin, andastromicin.
 38. The pharmaceutical composition of claim 36 wherein theaminoglycoside antibiotic is streptomycin.
 39. The pharmaceuticalcomposition of claim 36 wherein the aminoglycoside antibiotic isneomycin.
 40. The pharmaceutical composition of claim 36 wherein theaminoglycoside antibiotic is amikacin.
 41. The pharmaceuticalcomposition of claim 36 wherein the aminoglycoside antibiotic isgentamicin.
 42. The pharmaceutical composition of claim 36 wherein theaminoglycoside antibiotic is kanamycin.
 43. The pharmaceuticalcomposition of claim 36 wherein the aminoglycoside antibiotic istobramycin.
 44. The pharmaceutical composition of any one of claims35-43 formulated for oral, intravenous, intramuscular, or subcutaneousadministration.
 45. A method for protecting against kidney damage in anindividual receiving an aminoglycoside antibiotic comprisingadministering to the individual a therapeutically effective amount of acompound of any one of claims 1-34, or a pharmaceutically acceptablesalt, pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,and a pharmaceutically acceptable excipient.
 46. A method for preventingor treating hearing loss in an individual comprising administering tothe individual a therapeutically effective amount of a compound of anyone of claims 1-34, or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,and a pharmaceutically acceptable excipient.
 47. A method for preventingor treating sensory hair cell death in an individual comprisingadministering to the individual a therapeutically effective amount of acompound of any one of claims 1-34, or a pharmaceutically acceptablesalt, pharmaceutically acceptable solvate or hydrate, pharmaceuticallyacceptable salt hydrate, or pharmaceutically acceptable prodrug thereof,and a pharmaceutically acceptable excipient.
 48. The method of claim 46wherein the hearing loss is associated with exposure to an ototoxicagent.
 49. The method of claim 47 wherein the sensory hair cell death isassociated with exposure to an ototoxic agent.
 50. The method of claim48 or claim 49 wherein the ototoxic agent is an aminoglycosideantibiotic, chemotherapeutic agent, loop diuretic, antimalarialsesquiterpene lactone endoperoxide, antimalarial quinine, salicylate, orinterferon polypeptide.
 51. The method of claim 50 wherein the ototoxicagent is an aminoglycoside antibiotic.
 52. The method of claim 45 orclaim 51, wherein the aminoglycoside antibiotic is selected fromstreptomycin, neomycin, framycetin, paromomycin, paromomycin sulfate,ribostamycin, kanamycin, amikacin, arbekacin, bekanamycin, dibekacin,tobramycin, spectinomycin, hygromycin B, gentamicin, netilmicin,sisomicin, isepamicin, verdamicin, and astromicin.
 53. The method ofclaim 52, wherein the aminoglycoside antibiotic is streptomycin.
 54. Themethod of claim 52, wherein the aminoglycoside antibiotic is neomycin.55. The method of claim 52, wherein the aminoglycoside antibiotic isamikacin.
 56. The method of claim 52, wherein the aminoglycosideantibiotic is gentamicin.
 57. The method of claim 52, wherein theaminoglycoside antibiotic is kanamycin.
 58. The method of claim 52,wherein the aminoglycoside antibiotic is tobramycin.
 59. The method ofclaim 50, wherein the ototoxic agent is a chemotherapeutic agent. 60.The method of claim 59, wherein the chemotherapeutic agent is cisplatinor carboplatin.
 61. A compound of any one of claims 1-34, or apharmaceutically acceptable salt, pharmaceutically acceptable solvate orhydrate, pharmaceutically acceptable salt hydrate, or pharmaceuticallyacceptable prodrug thereof, with a maximum hair cell protection ofgreater than 50% in the assay described in Example
 12. 62. Use of theassay described in Example 12 for the testing of a compound of any oneof claims 1-34, or a pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate or hydrate, pharmaceutically acceptable salt hydrate,or pharmaceutically acceptable prodrug thereof.
 63. A process for thepreparation of(4R,7S)-2-(3-(4-chlorophenyl)ureido)-9-methyl-5,6,7,8-tetrahydro-4H-4,7-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride, comprising: A) the reaction of a compound with thestructure

with sodium borohydride in the presence of a solvent to produce acompound with the structure

B) followed by the reaction of the compound with the structure

with pyridine and methanesulfonyl chloride in the presence of a solvent,followed by treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) toproduce a compound with the structure

C) followed by the reaction of the compound with the structure

with an aqueous base and then an acid to produce a compound with thestructure

D) followed by the reaction of the compound with the structure

with sodium carbonate, 4-dimethylaminopyridine (DMAP), and diphenylphosphoryl azide (DPPA) in the presence of a solvent followed bytreatment with an acid to produce a compound with the structure

E) followed by the reaction of the compound with the structure

with malononitrile, sulfur, and morpholine to produce a compound withthe structure

F) followed by the reaction of the compound with the structure

with concentrated sulfuric acid to produce a compound with the structure

G) followed by the reaction of the compound with the structure

with 4-chlorophenyl isocyanate in the presence of a solvent to produce acompound with the structure

H) followed by the reaction of the compound with the structure

with hydrochloric acid in the presence of a solvent produce(4R,7S)-2-(3-(4-chlorophenyl)ureido)-9-methyl-5,6,7,8-tetrahydro-4H-4,7-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride having the structure


64. A process for the preparation of(4R,7S)-2-(3-(4-chlorophenyl)ureido)-9-methyl-5,6,7,8-tetrahydro-4H-4,7-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride, comprising: A) the reaction of a compound with thestructure

with sodium borohydride in the presence of a solvent to produce acompound with the structure

B) followed by the reaction of the compound with the structure

with pyridine and methanesulfonyl chloride in the presence of a solvent,followed by treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) toproduce a compound with the structure

C) followed by the reaction of the compound with the structure

with an aqueous base and then an acid to produce a compound with thestructure

D) followed by the reaction of the compound with the structure

with sodium carbonate, 4-dimethylaminopyridine (DMAP), and diphenylphosphoryl azide (DPPA) in the presence of a solvent followed bytreatment with an acid to produce a compound with the structure

E) followed by the reaction of the compound with the structure

with NCCH₂C(O)NH₂, sulfur, and morpholine to produce a compound with thestructure

F) followed by the reaction of the compound with the structure

with 4-chlorophenyl isocyanate in the presence of a solvent to produce acompound with the structure

G) followed by the reaction of the compound with the structure

with hydrochloric acid in the presence of a solvent produce(4R,7S)-2-(3-(4-chlorophenyl)ureido)-9-methyl-5,6,7,8-tetrahydro-4H-4,7-epiminocyclohepta[b]thiophene-3-carboxamidehydrochloride having the structure